WO2011094693A1 - Composés induisant l'interféron et leurs utilisations - Google Patents

Composés induisant l'interféron et leurs utilisations Download PDF

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Publication number
WO2011094693A1
WO2011094693A1 PCT/US2011/023187 US2011023187W WO2011094693A1 WO 2011094693 A1 WO2011094693 A1 WO 2011094693A1 US 2011023187 W US2011023187 W US 2011023187W WO 2011094693 A1 WO2011094693 A1 WO 2011094693A1
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WIPO (PCT)
Prior art keywords
vaccine
virus
compound
subject
interferon
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PCT/US2011/023187
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English (en)
Inventor
Adolfo Garcia-Sastre
Mila Ortigoza
Peter Palese
Megan Shaw
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Mount Sinai School Of Medicine
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Priority to US13/576,322 priority Critical patent/US20120308608A1/en
Publication of WO2011094693A1 publication Critical patent/WO2011094693A1/fr

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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
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Definitions

  • compositions comprising such Compounds and methods of using such Compounds to treat interferon-sensitive diseases such as viral infections, cancer, and multiple sclerosis.
  • Interferons are proteins made and released by the cells of most vertebrates in response to the presence of pathogens (e.g., bacteria and viruses) or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.
  • IFNs belong to the large class of glycoproteins known as cytokines and are typically divided among three classes: Type I IFN (IFN-I), Type II IFN (IFN-II), and Type III IFN (IFN-III).
  • IFN-stimulated genes IFN-stimulated genes
  • IFN immunodeficiency virus
  • hepatitis B see Perrillo, Hepatology, 2009. 49(5 Suppl):S103-l 1
  • West Nile see Anderson et al., Emerg Infect Dis, 2002. 8(1): 107-8
  • SARS see Cinatl et al., Expert Opin Biol Ther, 2004. 4(6):827-36.
  • IFN due to the ability of IFNs to improve the immune system response against cancer cells and act directly on cancer cells by slowing their growth and/or promoting their development into cells with more normal behavior, IFN has been administered to treat cancer patients. Interferon also has been used to treat other diseases and conditions, such as multiple sclerosis.
  • IFNs are believed to stimulate natural killer cells, T cells, and macrophages, thus boosting the immune system's anticancer function.
  • IFN endogenous IL-12
  • IFN interleukin-12
  • IFN-inducting Compounds also have potential to serve as adjuvants in vaccine preparations, as well as in combination with other anti-cancer therapies.
  • Compound to a subject in need of such treatment.
  • a Compound can be administered as a single-agent therapy to a subject in need of such treatment.
  • a Compound can be administered in combination with one or more additional therapies to a subject in need of such treatment.
  • a method of treating an interferon-sensitive disease or a symptom associated therewith in a subject comprising administering to a subject in need thereof an effective amount of a Compound.
  • the interferon-sensitive disease is a viral disease.
  • the interferon-sensitive disease is cancer.
  • the interferon-sensitive disease is a bacterial disease.
  • the interferon-sensitive disease is multiple sclerosis.
  • the interferon-sensitive disease is a viral disease.
  • the interferon-sensitive disease is cancer.
  • the interferon-sensitive disease is a bacterial disease.
  • the interferon-sensitive disease is multiple sclerosis.
  • a method of inhibiting or reducing replication of a virus in a subject comprising administering to a subject in need thereof an effective amount of a Compound.
  • a method of inhibiting or reducing replication of an influenza virus in a subject comprising administering to a subject in need thereof an effective amount of a Compound.
  • provided herein is a method of treating an influenza virus infection or a symptom associated therewith in a subject, comprising administering to a subject in need thereof an effective amount of a Compound.
  • a method of preventing a symptom associated with an influenza virus infection in a subject comprising administering to a subject in need thereof an effective amount of a Compound.
  • provided herein is a method of treating an influenza virus disease in a subject, comprising administering to a subject in need thereof an effective amount of a Compound.
  • a method of preventing a symptom associated with an influenza virus disease in a subject comprising administering to a subject in need thereof an effective amount of a Compound.
  • a Compound is used as an adjuvant.
  • a Compound is administered as an adjuvant with a vaccine.
  • the vaccine is a viral vaccine.
  • the vaccine is not a viral vaccine.
  • the vaccine is a live, attenuated viral vaccine.
  • the vaccine is an inactivated or killed viral vaccine.
  • a Compound is used to induce interferon in cultured cells.
  • the cultured cells are cultured in a bioreactor.
  • a Compound is used to induce the production of recombinant interferon by cultured cells.
  • the interferon produced by the cultured cells is isolated/purified.
  • the interferon produced by the cultured cells is collected and used for a secondary application.
  • a Compound induces interferon production in the presence of virus and is sometimes referred to herein as "Compound I.”
  • a Compound induces interferon production independent of virus infection. In other words, interferon production is induced in the presence or absence of virus infection. Such compounds are referred to herein as "Compound II.”
  • a Compound is purified/isolated.
  • an "effective amount" in the context of administering a treatment/therapy to a subject refers to the amount of a treatment which has a prophylactic and/or therapeutic effect(s).
  • an "effective amount" in the context of administration of a treatment/therapy to a subject with an interferon-sensitive disease refers to the amount of a treatment which is sufficient to achieve one, two, three, four, or more of the following effects: (i) reduce or ameliorate the severity of an interferon-sensitive disease or a symptom or disease associated therewith; (ii) reduce the duration of an interferon-sensitive disease or a symptom or disease associated therewith; (iii) reduce or prevent the progression of an interferon-sensitive disease or a symptom or disease associated therewith; (iv) cause regression of an interferon-sensitive disease or a symptom or disease associated therewith; (v) prevent the development or onset of an interferon-sensitive disease or a symptom or disease associated therewith; (vi)
  • yielderly human refers to a human 65 years or older.
  • human infant refers to a newborn to 1 year old year human.
  • human child refers to a human that is 1 year to 18 years old.
  • human adult refers to a human that is 18 years or older.
  • the term "in combination,” in the context of the administration of a Compound refers to the administration of a Compound prior to, concurrently with, or subsequent to the administration of one or more additional treatments/therapies (e.g., agents, surgery, or radiation).
  • additional treatments/therapies e.g., agents, surgery, or radiation.
  • the use of the term “in combination” does not restrict the order in which therapies are administered to a subject.
  • the interval of time between the administration of a Compound and the administration of one or more additional therapies may be about 1-5 minutes, 1-30 minutes, 30 minutes to 60 minutes, 1 hour, 1-2 hours, 2-6 hours, 2-12 hours, 12-24 hours, 1-2 days, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 15 weeks, 20 weeks, 26 weeks, 52 weeks, 11-15 weeks, 15-20 weeks, 20-30 weeks, 30-40 weeks, 40-50 weeks, 1 month, 2 months, 3 months, 4 months 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1 year, 2 years, or any period of time in between.
  • a Compound and one or more additional therapies are administered less than 1 day, 1 week, 2 weeks, 3 weeks, 4 weeks, one month, 2 months, 3 months, 6 months, 1 year, 2 years, or 5 years apart.
  • an infection means the invasion by, multiplication and/or presence of a pathogen in a cell, tissue, or subject.
  • an infection is an "active" infection, i.e., one in which the pathogen is replicating in a cell, tissue, or subject.
  • Such an infection may be characterized by the spread of the pathogen to other cells, tissues, organs, and/or subjects from the cells, tissues, organs, and/or subjects initially infected by the pathogen.
  • An infection may also be a latent infection, i.e., one in which the pathogen is not replicating.
  • an infection refers to the pathological state resulting from the presence of the pathogen in a cell, tissue, or subject, or by the invasion of a cell, tissue, or subject by the pathogen.
  • interferon and “IFN” refer to an interferon of any type, e.g., type I interferon, type II interferon, and type III interferon.
  • interferon also refers to interferon subtypes including, but not limited to IFN-a, IFN- ⁇ and IFN- ⁇ .
  • Compound that induces interferon production describes a Compound that causes the production of interferon (e.g., production of an interferon protein).
  • Interferon-sensitive disease refers to a disease or condition in which the presence of and/or production of interferon has a beneficial effect.
  • Interferon-sensitive diseases include, but are not limited to, diseases and/or infections caused by pathogens (such as viral diseases and bacterial diseases); cancers (e.g., leukemia and lymphomas including hairy cell leukemia, chronic myeloid leukemia, nodular lymphoma, cutaneous T-cell lymphoma); and autoimmune disorders (e.g., multiple sclerosis).
  • log refers to logio
  • MOI multiplicity of infection
  • the MOI is determined by dividing the number of pathogens added (ml added x PFU) by the number of cells added (ml added x cells/ml).
  • Suitable pharmaceutically acceptable base addition salts for a Compound include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, ⁇ , ⁇ '-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p- toluenesulfonic acid.
  • inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic
  • Specific non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric, and methanesulfonic acids.
  • Examples of specific salts thus include hydrochloride and mesylate salts.
  • Other examples of salts are well known in the art, see, e.g., Remington 's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).
  • the term "purified,” in the context of a Compound that is chemically synthesized, refers to a Compound that is substantially free of chemical precursors or other chemicals when chemically synthesized. As used in this context, substantially means less than 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, or 1% chemical precursors or other chemicals.
  • a Compound is 60%, preferably 65%, 70%, 75%, 80%, 85%, 90%, or 99% free of other, different Compounds.
  • contaminating materials from the natural source e.g., soil particles, minerals, chemicals from the environment, and/or cellular materials from the natural source, such as but not limited to cell debris, cell wall materials, membranes, organelles, the bulk of the nucleic acids, carbohydrates, proteins, and/or lipids present in cells.
  • substantially free of natural source materials refers to preparations of a Compound that has been separated from the material ⁇ e.g., cellular components of the cells) from which it is isolated.
  • a Compound that is isolated includes preparations of a Compound having less than about 30%>, 20%>, 10%>, 5%>, 2%>, or 1%> (by dry weight) of cellular materials and/or contaminating materials.
  • the terms “subject” or “patient” are used interchangeably.
  • the term “subject” refers to an animal ⁇ e.g., bird, reptile, mammal).
  • a subject is a mammal including a non-primate ⁇ e.g., camel, donkey, zebra, cow, pig, horse, goat, sheep, cat, dog, rat, mouse) and a primate ⁇ e.g., a monkey, chimpanzee, human).
  • a subject is a human.
  • a subject is a farm animal.
  • a subject is a household pet.
  • substituted means a group substituted by one to four or more substituents, such as, halo, trifluoromethyl,
  • CONH 2 substituted carbamyl (e.g., CONH alkyl, CONH aryl, CONH aralkyl or instances where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl), alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocyclo, such as, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.
  • substituted carbamyl e.g., CONH alkyl, CONH aryl, CONH aralkyl or instances where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl
  • alkoxycarbonyl aryl, substituted aryl, guanidino and heterocyclo, such as, indolyl, imidazolyl, furyl, thieny
  • premature human infant refers to a human infant born at less than 37 weeks of gestational age.
  • the terms “therapies” and “therapy” can refer to any protocol(s), method(s), composition(s), formulation(s), and/or agent(s) that can be used in the prevention, treatment, management, or amelioration of a condition or disorder or a symptom thereof (e.g., an interferon-sensitive disease or a symptom associated therewith).
  • the terms “therapies” and “therapy” refer to a drug therapy, adjuvant therapy, radiation, surgery, biological therapy, supportive therapy, and/or other therapies useful in treatment, management, prevention, or amelioration of a condition or disorder or a symptom thereof (e.g., an interferon-sensitive disease or a symptom or disease associated therewith).
  • the term “therapy” refers to a Compound or a pharmaceutical composition thereof.
  • the term “therapy” refers to a therapy other than a Compound or a pharmaceutical composition thereof.
  • an interferon-sensitive disease or a symptom associated therewith e.g., an interferon-sensitive disease or a symptom
  • a therapy refers to a therapy other than a treatment using a Compound or a pharmaceutical composition thereof.
  • a therapy includes the use of a Compound as an adjuvant therapy. For example, using a Compound in conjunction with a drug therapy, biological therapy, surgery, and/or supportive therapy.
  • the term means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 4 carbon atoms.
  • Representative saturated straight chain Ci -4 alkyls include -methyl, -ethyl, -n-propyl and -n- butyl.
  • An alkyl group can be unsubstituted or substituted.
  • C2- 4 alkenyl means a straight chain or branched non-cyclic hydrocarbon having from 2 to 4 carbon atoms and including at least one carbon-carbon double bond.
  • Representative straight chain and branched C 2- 4 alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl and -isobutylenyl.
  • the double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group.
  • An alkenyl group can be unsubstituted or substituted.
  • each "alkyl” is independently an alkyl group as defined above, including -CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , -(CH 2 ) 2 OCH 2 CH 3 , -(CH 2 ) 2 0(CH 2 ) 2 CH 3 , and the like.
  • aryl means a carbocyclic aromatic ring containing from 5 to 14 ring atoms.
  • the ring atoms of a carbocyclic aryl group are all carbon atoms.
  • Aryl ring structures include Compounds having one or more ring structures such as mono-, bi-, or tricyclic Compounds as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl and the like.
  • the aryl group is a monocyclic ring or bicyclic ring.
  • aryl groups include phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, phenanthrenyl and naphthyl.
  • a carbocyclic aryl group can be unsubstituted or substituted.
  • heteroaryl means a carbocyclic aromatic ring containing from 5 to 14 ring atoms and the ring atoms contain at least one heteroatom, preferably 1 to 3 heteroatoms, independently selected from nitrogen, oxygen, or sulfur.
  • Heteroaryl ring structures include Compounds having one or more ring structures such as mono-, bi-, or tricyclic Compounds as well as fused heterocycle moities.
  • heteroaryls are triazolyl, tetrazolyl, oxadiazolyl, pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, benzoisoxazolyl, benzoisothiazolyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzoquinazolinyl, acridinyl, pyrimidyl and oxazolyl.
  • a group can be unsubstituted or substituted.
  • arylalkyl means -(alkyl)- (aryl), wherein alkyl and aryl are defined above, including, but not limited to -(CH 2 )phenyl, - (CH 2 ) 2 phenyl, -(CH 2 ) 3 phenyl, -CH(phenyl) 2 , -CH(phenyl) 3 , -(CH 2 )tolyl, -(CH 2 )anthracenyl, -(CH 2 )fluorenyl, -(CH 2 )indenyl, -(CH 2 )azulenyl, -(CH 2 )naphthyl, and the like.
  • heterocyclyl means a monocyclic or polycyclic ring comprising carbon and hydrogen atoms, optionally having 1 to 4 multiple bonds, and the ring atoms contain at least one heteroatom, in one embodiment 1 to 3 heteroatoms, independently selected from nitrogen, oxygen, and sulfur.
  • Heterocyclyl ring structures include Compounds having one or more ring structures such as mono-, bi-, or tricylic Compounds.
  • the heterocyclyl group is a monocyclic ring or bicyclic ring.
  • heterocycles include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl,
  • a heterocyclyl ring can be unsubstituted or substituted.
  • heterocyclylalkyl means -(alkyl)-(heterocyclyl), wherein alkyl and heterocyclyl are defined above. Substituted heterocyclylalkyl groups may be substituted at the alkyl, the heterocyclyl, or both the alkyl and the heterocyclyl portions of the group. In one embodiment, the heterocylylalkyl group is ethyl-morpholinyl.
  • arylcarbonyl means - C(0)(aryl), wherein aryl is defined above, including -C(0)(phenyl), -C(0)(tolyl), - C(0)(anthracenyl), -C(0)(fluorenyl), -C(0)(indenyl), -C(0)(azulenyl), -C(0)(naphthyl), and the like.
  • the MDCK-IFNb-Luc reporter cell line was used to monitor Compounds that relieve the luciferase reporter from inhibition by virally encoded NS 1 protein. This system is not responsive to infection with a wild type virus, e.g., A/PR/8/34 (left panel), but only to infection with a mutant NSl -containing virus (middle panel) or with a wild-type virus in the presence of an NSl inhibitor (right panel). Positive control and positive readout cells indicate a positive induction of the reporter.
  • B Response of the MDCK-IFNb-Luc reporter cell line to infection with decreasing amounts of A/PR/8/34 virus and NSl truncated versions of this virus.
  • Sendai virus (SeV) was used as a positive control.
  • FIG. 1 A) Pie diagram of the two classes of Compounds screened. Compounds with known biological activity made up 3.1% of the total number, while the majority of Compounds screened had unknown properties.
  • B Schematic for HT Compound Screen.
  • C Formula used to calculate the Z score.
  • D Graph of all the average Z score of all Compound-containing wells from the primary screen. Compounds defined as hits are bracketed. Hit criteria was not based on the average Z score, but on individual Z score of each individual duplicate.
  • FIG. 3 Confirmation screen for hit Compounds: (A) Cytotoxicity graphs for two representative hit Compounds. (B) Dose-dependent induction of IFNb-luc reporter expression for two representative hit Compounds. The top panels depict a Compound that depends on influenza A/PR/8/34 virus infection to induce IFN, whereas the bottom panels depict a Compound that induces IFN independent of virus. ASN2 represents Compound 1 (see Table 1). ENA51 represents Compound 28 (see Table 2).
  • IFN bioassay Controls for the IFN bioassay.
  • IFN-treated MDCK cells and untreated cells were used as controls.
  • ASN2 is able to induce the production of IFN only if the treated cells are infected with influenza A/PR/8/34 virus. Fluorescent images of the wells are shown in the right panels for both sections, representing the growth of VSV- GFP.
  • FIG. ASN2 attenuates influenza virus replication: Influenza A/PR/8/34 (left) and A/WSN/33 (right) virus replication is attenuated in the presence of ASN2
  • FIG. 1 ASN possesses antiviral activity: Influenza A/Vietnam/ 1203/2004 (H5N1) virus replication is attenuated in the presence of ASN2.
  • FIG. 7 Broad antiviral activity of ASN2: ASN2 is capable of inhibiting the replication of multiple strains and subtypes of influenza A virus.
  • FIG 8. ASN2 affects viral replication machinery: The viral replication machinery of an influenza virus mini-genome is inhibited by ASN2, as indicated by decreasing levels of luciferase activity in the presence of increasing ASN2 concentrations.
  • Figure 9. Inhibition of viral replication by ASN2 is not dependent on type I interferon: ASN2 inhibits viral replication in interferon competent cells (MDCK and A549) as well as interferon-deficient cells (Vero).
  • FIG. 10 Interferon induction and cytotoxicity of Compounds: 24 compounds were identified as being able to induce interferon in the absence of virus; the levels of interferon induction and cytotoxicity of the compounds is presented.
  • FIG. 12 Interferon Induction and antiviral activity of Compounds in human cells: Sixteen of the 24 compounds identified as being able to induce interferon in the absence of virus in MDCK cells induced interferon in human 293T and A549 cells (left panel). Four of these compounds possessed antiviral activity against vesicular stomatitis virus grown in the same human cells (right panel).
  • the present application is based, in part, on the discovery of Compounds that induce the production of interferon and that such Compounds can be used to treat interferon- sensitive diseases.
  • Compound to a subject in need of such treatment.
  • a Compound can be administered as a single-agent therapy to a subject in need of such treatment.
  • a Compound can be administered in combination with one or more additional therapies to a subject in need of such treatment.
  • a Compound is used as an adjuvant.
  • a Compound is administered as an adjuvant with a vaccine.
  • the vaccine is a viral vaccine.
  • the vaccine is not a viral vaccine.
  • the vaccine is a live, attenuated viral vaccine.
  • the vaccine is a non-live viral vaccine.
  • a Compound is used to induce interferon in cultured cells.
  • the cultured cells are cultured in a bioreactor.
  • a Compound is used to induce the production of recombinant interferon by cultured cells.
  • the interferon produced by the cultured cells is isolated/purified.
  • the interferon produced by the cultured cells is collected and used for a secondary application.
  • Compounds that induce interferon in the presence of a virus e.g., an influenza virus
  • a virus e.g., an influenza virus
  • Compound I include the Compounds of Table 1, below.
  • Compound II Compounds that induce interferon independent of virus infection
  • Compound II includes those of Formula I:
  • R 1 is substituted or unsubstituted heterocyclyl
  • R 2 is H or OH
  • R 1 is substituted tetrahydro-2H-pyran.
  • Compound II includes those of Formula II:
  • X is CH or N
  • R 1 , R 2 , R 3 and R 4 are at each occurrence independently hydrogen or substituted or unsubstituted Ci -4 alkyl.
  • R 1 , R 2 , R 3 and R 4 are each hydrogen.
  • R 1 , R 2 , R 3 and R 4 are each methyl.
  • Compound II includes those of Formula III:
  • R 1 and R 2 are at each occurrence independently substituted or unsubstituted Ci_
  • R 1 and R 2 are each ethyl.
  • R 1 and R 2 taken together with the nitrogen atom to which they are attached form piperidine.
  • Compound II includes those of Formula IV:
  • R 1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl
  • R 2 is substituted or unsubstituted Ci -4 alkyl, substituted or unsubstituted C 2-
  • R 1 is furan
  • R 1 is thiophene.
  • R 1 is phenyl
  • R 2 is arylalkyl
  • R 2 is allyl
  • R 2 is propyl
  • R 2 is alkoxyalkyl
  • Compound II includes those of Formula V:
  • R 1 is substituted or unsubstituted Ci -4 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted
  • heterocyclyl -NH(substituted or unsubstituted heteroaryl) or -NH(substituted or
  • R 2 is cyano, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted hydrazine or arylcarbonyl.
  • R 1 is furan
  • R 1 is thiophene. [00100] In another embodiment, R 1 is phenyl.
  • R 1 is piperidine.
  • R 1 is -NH(2,3-dihydrobenzo[b][l,4]dioxine).
  • R 1 is 3,4-dihydroquinoxalin-2(lH)-one.
  • R 1 is 1,2,3,4-tetrahydroisoquinoline.
  • R 1 is methyl
  • R 2 is arylalkyl
  • R 2 is heterocyclylalkyl.
  • R 2 is allyl
  • R 2 is propyl
  • R 2 is alkoxyalkyl
  • R 2 is lH-pyrazolo[3,4-d]pyrimidin-4(5H)-imine.
  • R 2 is 3,4-dihydroisoquinoline.
  • R 2 is quinazolin-4(3H)-one.
  • R 2 is 1,3,4-thiadiazole.
  • R 2 is lH-benzo[d]imidazole.
  • R 2 is triazole
  • Compound II includes doxorubicin, doxorubicin-HCl, daunorubicin-HCl, aminacrine, acrisorcin, aklavin-HCl and ellipticine and pharmaceutically acceptable salts or stereoisomers, including enantiomers, diastereomers, racemates or mixtures of stereoisomers, thereof.
  • Compound II include the Compounds of Table 2, below.
  • the Compounds do not include one or more of doxorubicin, doxorubicin-HCl, daunorubicin-HCl, aminacrine, acrisorcin, aklavin-HCl and ellipticine and pharmaceutically acceptable salts or stereoisomers, including enantiomers, diastereomers, racemates or mixtures of stereoisomers, thereof.
  • the compound of formula I is not doxorubicin or daunorubicin and the compound of formula II is not aminacrine.
  • Compounds provided herein can be obtained via standard, well-known synthetic methodology, see e.g., March, J. Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992. Starting materials useful for preparing Compounds provided herein are commercially available or can be prepared from commercially available materials using known synthetic methods and reagents.
  • Two or more Compounds provided herein can be administered in combination with each other, either concomitantly or sequentially.
  • aminacrine and acriorcine are administered in combination.
  • the ability of a compound to induce interferon production can be assessed by any method known in the art for measuring protein levels, such as immunoprecipitation, Western blot analysis (immunoblotting), enzyme-linked immunosorbent assay (ELISA), quantitative protein assays, protein activity assays (for example, histone deacetylase activity), immunohistochemistry, immunocytochemistry or fluorescence-activated cell sorting (FACS).
  • Antibodies directed to a target e.g., interferon, can be identified and obtained from a variety of sources, such as the MSRS catalog of antibodies (Aerie Corporation, Birmingham, MI), or can be prepared via conventional monoclonal or polyclonal antibody generation methods well known in the art.
  • RNA levels of interferon production are assessed by measuring levels of interferon at the RNA level using methods known to those of skill in the art.
  • RNA levels can be quantified by routine methods such as of Northern blot analysis, competitive polymerase chain reaction (PCR), or quantitative (e.g., real-time) PCR.
  • PCR competitive polymerase chain reaction
  • RNA analysis can be performed on a selected nucleic acid population, for example, total cellular and/or viral RNA, RNAs with a certain size cut-off, etc.
  • the ability of a compound to induce interferon production is assessed using a modified functional interferon bioassay (see, e.g., Park et al., J Virol, 2003. 77(2): 1501-1 1 ; and Iwata et al, J Vet Med Sci, 1996. 58(1)23-7).
  • a modified functional interferon bioassay see, e.g., Park et al., J Virol, 2003. 77(2): 1501-1 1 ; and Iwata et al, J Vet Med Sci, 1996. 58(1)23-7.
  • wells of plates are seeded with cells, e.g., MDCK cells, and the cells are allowed to incubate for -20-24 hours at 37°C, 5% C0 2 . The cells then are treated with compounds of interest.
  • the cells Two hours after treatment, the cells are either mock infected or infected with virus added directly into the media and incubated for -18-20 hours at 37°C, 5% C0 2 .
  • Supernatant from the treated/infected cells (containing interferon) is transferred into a new plate and UV inactivated. Dilutions are made with the UV-inactivated supernatants. These dilutions are overlaid onto fresh cells that are plated the previous day, and left to incubate for -20-24 hours at 37°C, 5% C0 2 .
  • reporter protein e.g., GFP
  • GFP reporter protein-expressing virus
  • Replication of the reporter protein-expressing viruses, such as GFP-expressing viruses can be is monitored by measuring the relative fluorescence of the reporter protein in a plate reader, thus allowing for determination of whether IFN is present in the supernatant of the virus-infected cells and thus whether the compound induced IFN production.
  • the ability of a compound to induce interferon production is assessed using an assay comprising cells engineered to express a reporter gene (e.g., a luciferase reporter gene) operably linked to an interferon promoter.
  • a cell expressing a reporter gene e.g., a luciferase reporter gene
  • the ability of the compound to induce interferon production then can be assessed by measuring the level of reporter gene activity in the presence of the compound and comparing it to the level of reporter gene activity in the absence of a compound or in the presence of a negative control. Methods for measuring reporter gene activity are well-known in the art.
  • Compounds preferentially affect the viability of cells affected by an interferon-sensitive disease. In specific embodiments, Compounds are not so cytotoxic that they are unsafe for administration to an animal or human subject with an interferon-sensitive disease.
  • cell proliferation can be assayed by measuring Bromodeoxyuridine (BrdU) incorporation ⁇ See, e.g., Hoshino et al, 1986, Int. J. Cancer 38, 369; Campana et al, 1988, J. Immunol. Meth. 107:79), (3H) thymidine incorporation (See, e.g., Chen, J., 1996, Oncogene 13: 1395-403; Jeoung, J., 1995, J. Biol. Chem.
  • RNA and mRNA and activity can be determined by any method well known in the art.
  • protein can be quantitated by known immunodiagnostic methods such as ELISA, Western blotting or immunoprecipitation using antibodies, including commercially available antibodies.
  • mRNA can be quantitated using methods that are well known and routine in the art, for example, using northern analysis, RNase protection, or polymerase chain reaction in connection with reverse transcription.
  • Cell viability can be assessed by using trypan-blue staining or other cell death or viability markers known in the art.
  • the level of cellular ATP is measured to determined cell viability.
  • cell viability is measured in three-day and seven-day periods using an assay standard in the art, such as the CellTiter-Glo Luminescent Cell Viability Assay Kit (Promega, Madison, WI) which measures levels of intracellular ATP. A reduction in cellular ATP is indicative of a cytotoxic effect.
  • cell viability can be measured in the neutral red uptake assay.
  • visual observation for morphological changes may include enlargement, granularity, cells with ragged edges, a filmy appearance, rounding, detachment from the surface of the well, or other changes.
  • CC 50 cell inhibitory (cytotoxic) concentration
  • compounds have an CC 50 of at least 150 ⁇ , 175 ⁇ , 200 ⁇ , 225 ⁇ , 250 ⁇ , 300 ⁇ , 325 ⁇ , or 350 ⁇ .
  • compounds have an CC 50 in the range of 150 ⁇ to 200 ⁇ , 150 ⁇ to 300 ⁇ , 200 ⁇ to 300 ⁇ , 250 ⁇ to 300 ⁇ , 300 ⁇ to 400 ⁇ , 350 ⁇ to 450 ⁇ , or 375 ⁇ to 500 ⁇ .
  • the cells used in the cytotoxicity assay are animal cells, including primary cells and cell lines. In some embodiments, the cells are human cells. In certain embodiments, cytotoxicity is assessed in one or more of the following cell lines: U937, a human monocyte cell line; primary peripheral blood mononuclear cells (PBMC); Huh7, a human hepatoblastoma cell line; 293T, a human embryonic kidney cell line; or THP- 1, monocytic cells. In certain embodiments, cytotoxicity is assessed in one or more of the following cell lines: MDCK, MEF, Huh 7.5, Detroit, or human tracheobronchial epithelial (HTBE) cells.
  • PBMC primary peripheral blood mononuclear cells
  • Huh7 a human hepatoblastoma cell line
  • 293T a human embryonic kidney cell line
  • THP- 1, monocytic cells THP- 1, monocytic cells.
  • cytotoxicity is assessed in one or more of the following cell lines:
  • Compounds can be tested for in vivo toxicity in animal models.
  • animal models described herein and/or known in the art, used to test the activities of
  • Compounds can also be used to determine the in vivo toxicity of these Compounds. For example, animals are administered a range of concentrations of Compounds. Subsequently, the animals are monitored over time for lethality, weight loss or failure to gain weight, and/or levels of serum markers that may be indicative of tissue damage ⁇ e.g., creatine phosphokinase level as an indicator of general tissue damage, level of glutamic oxalic acid transaminase or pyruvic acid transaminase as indicators for possible liver damage). These in vivo assays may also be adapted to test the toxicity of various administration mode and/or regimen in addition to dosages.
  • tissue damage e.g., creatine phosphokinase level as an indicator of general tissue damage, level of glutamic oxalic acid transaminase or pyruvic acid transaminase as indicators for possible liver damage.
  • These in vivo assays may also be adapted to test the toxicity of
  • the toxicity and/or efficacy of a Compound can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g. , for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 50 /ED 50 .
  • a Compound that exhibits large therapeutic indices is preferred. While a Compound that exhibits toxic side effects may be used, care should be taken to design a delivery system that targets such agents to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.
  • the selective index of Compounds can also be assessed by determining the cytotoxic index (CCsoVICso ratio.
  • the selective index (CC 50 /IC 50 ) of Compounds is at least 25, 50, 75, 100, 125, or 150.
  • the selective index (CC50/IC50) of Compounds is in the range of 50 to 75, 50 to 100, or 75 to 125.
  • the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage of a Compound identified in accordance with the embodiments described herein for use in humans.
  • the dosage of such agents lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC 50 (i.e., the concentration of the test Compound that achieves a half- maximal inhibition of symptoms) as determined in cell culture.
  • IC 50 i.e., the concentration of the test Compound that achieves a half- maximal inhibition of symptoms
  • levels in plasma may be measured, for example, by high-performance liquid chromatography.
  • the effect of a Compound on virus replication can be assessed by any assay known in the art.
  • the cells can be infected at different MOIs and the effect of a Compound on virus replication can be assessed.
  • the MOIs may be 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 2.5, or 5 or greater.
  • the effect of different concentrations of a Compound on virus replication can also be assessed.
  • the cells or other substrate that contains cells (e.g., embryonated eggs) used in the assay should be susceptible to infection by the virus (e.g., influenza virus).
  • the cells may be primary cells or established cell lines. In one
  • the cell or cell line is biologically relevant to virus infection.
  • virus replication can be measured at different times post-infection. For example, virus replication may be measured 6 hours, 12 hours, 16 hours, 24 hours, 48 hours or 72 hours post-infection. Any method known to one of skill in the art can be used measure virus replication.
  • a Compound is considered to reduce or inhibit viral replication if it inhibits or reduces viral replication (i.e., the production of viral particles) by at least 1.5 fold, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 25 fold, 30 fold, 35 fold, 40 fold, 45 fold, 50 fold, 100 fold, 500 fold, or 1000 fold relative to virus replication in the absence of Compound or the presence of a negative control.
  • viral replication i.e., the production of viral particles
  • a Compound is considered to reduce or inhibit viral replication if it reduces the virus replication by 1.5 to 3 fold, 2 to 4 fold, 3 to 5 fold, 4 to 8 fold, 6 to 9 fold, 8 to 10 fold, 2 to 10 fold, 5 to 20 fold, 10 to 40 fold, 10 to 50 fold, 25 to 50 fold, 50 to 100 fold, 75 to 100 fold, 100 to 500 fold, 500 to 1000 fold, or 10 to 1000 fold relative to virus replication in the absence of Compound or the presence of a negative control.
  • a Compound is considered to reduce or inhibit viral replication if it reduces the virus replication by approximately 2 logs or more, approximately 3 logs or more,
  • a Compound is considered to reduce or inhibit viral replication if it reduces the replication of a viral genome by about at least 1.5 fold, 2, fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 25 fold, 30 fold, 35 fold, 40 fold, 45 fold, 50 fold, 75 fold, 100 fold, 500 fold, or 1000 fold relative to replication of the viral genome in the absence of a Compound or relative to a negative control in an assay described herein or others known to one of skill in the art.
  • a Compound is considered to reduce or inhibit viral replication if it reduces the replication of a viral genome by about at least 1.5 fold, 2, fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 25 fold, 30 fold, 35 fold, 40 fold, 45 fold, 50 fold, 75 fold, 100 fold, 500 fold, or 1000 fold relative to replication of the viral genome in the absence of a Compound or relative to a negative control in an
  • Compound is considered to reduce or inhibit viral replication if it reduces the replication of a viral genome by about 1.5 to 3 fold, 2 to 4 fold, 3 to 5 fold, 4 to 8 fold, 6 to 9 fold, 8 to 10 fold, 2 to 10 fold, 5 to 20 fold, 10 to 40 fold, 10 to 50 fold, 25 to 50 fold, 50 to 100 fold, 75 to 100 fold, 100 to 500 fold, 500 to 1000 fold, or 10 to 1000 fold relative to replication of the viral genome in the absence of a Compound or relative to a negative control in an assay described herein or others known to one of skill in the art.
  • a negative control in an assay described herein or others known to one of skill in the art in certain embodiments, a
  • Compound is considered to reduce or inhibit viral replication if it reduces the replication of a viral genome by at least 1 log, 1.5 logs, 2 logs, 2.5 logs, 3 logs, 3.5 logs, 4 logs, 4.5 logs, 5 logs or more relative to replication of the viral genome in the absence of a Compound or relative to a negative control in an assay described herein or others known to one of skill in the art.
  • a Compound is considered to reduce or inhibit viral replication if it reduces the synthesis of viral proteins by at least 1.5 fold, 2, fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 25 fold, 30 fold, 35 fold, 40 fold, 45 fold, 50 fold, 75 fold, 100 fold, 500 fold, or 1000 fold relative to the synthesis of viral proteins in the absence of a Compound or relative to a negative control in an assay described herein or others known to one of skill in the art in an assay described herein or others known to one of skill in the art.
  • a Compound is considered to reduce or inhibit viral replication if it reduces the synthesis of viral proteins at least 1.5 to 3 fold, 2 to 4 fold, 3 to 5 fold, 4 to 8 fold, 6 to 9 fold, 8 to 10 fold, 2 to 10 fold, 5 to 20 fold, 10 to 40 fold, 10 to 50 fold, 25 to 50 fold, 50 to 100 fold, 75 to 100 fold, 100 to 500 fold, 500 to 1000 fold, or 10 to 1000 fold relative to the synthesis of viral proteins in the absence of a Compound or relative to a negative control in an assay described herein or others known to one of skill in the art.
  • a Compound is considered to reduce or inhibit viral replication if it reduces the synthesis of viral proteins approximately 1 log, 1.5 logs, 2 logs, 2.5 logs, 3 logs, 3.5 logs, 4 logs, 4.5 logs, 5 logs relative to the synthesis of viral proteins in the absence of a Compound or relative to a negative control in an assay described herein or others known to one of skill in the art.
  • a Compound is considered to reduce or inhibit viral replication if it results in 1.5 fold or more, 2 fold or more, 3 fold or more, 4 fold or more, 5 fold or more, 6 fold or more, 7 fold or more, 8 fold or more, 9 fold or more, 10 fold or more, 15 fold or more, 20 fold or more, 25 fold or more, 30 fold or more, 35 fold or more, 40 fold or more, 45 fold or more, 50 fold or more, 60 fold or more, 70 fold or more, 80 fold or more, 90 fold or more, or 100 fold or more reduction of viral yield per round of viral replication.
  • a Compound results in about a 2 fold or more reduction of viral yield per round of viral replication.
  • a Compound is considered to reduce or inhibit viral replication if it results in a 2 to 4, 2 to 5, 3 to 5, or 5 to 10 fold reduction of viral yield per round of viral replication. In a specific embodiment, a Compound results in about a 10 fold or more reduction of viral yield per round of viral replication.
  • a Compound is considered to reduce or inhibit viral replication if it reduces viral replication by at least 2 wells of hemagglutinin (HA) in a hemagglutination assay, which equals approximately a 75% reduction in viral titer.
  • HA hemagglutinin
  • a Compound is considered to reduce or inhibit viral replication if it reduces viral titer by 50%> or more, by 55%> or more, by 60%> or more, by 65 %> or more, by 70%> or more, by 75%> or more, by 80%> or more, by 85%> or more, by 90%> or more, or by 95%> or more.
  • a Compound is considered to reduce or inhibit viral replication if it reduces viral titer approximately 1 log, 1.5 logs, 2 logs, 2.5 logs, 3 logs, 3.5 logs, 4 logs, 4.5 logs, 5 logs relative to the viral titer in the absence of a Compound or relative to a negative control in an assay described herein or others known to one of skill in the art.
  • a Compound is considered to reduce or inhibit viral replication if it reduces viral titer approximately 2 to 5, 3 to 5, 4 to 5, or 5 to 10 logs relative to the viral titer in the absence of a Compound or relative to a negative control in an assay described herein or others known to one of skill in the art.
  • the effect of a Compound on the replication of an influenza virus is determined. Standard assays for influenza virus replication have been described (see, e.g., Sidwell et ah, Antiviral Research, 2000, 48: 1-16).
  • the effect of a Compound on the replication of an influenza A virus is determined.
  • the effect of a Compound on the replication of an influenza B virus is determined.
  • the effect of a Compound on the replication of an influenza C virus is determined.
  • the effect of a Compound on the replication of a currently circulating influenza virus is determined.
  • the effect of a Compound on replication of HlNl influenza virus is determined.
  • the effect of a Compound on replication of H5N1 influenza virus is determined. In some embodiments, the effect of a Compound on replication of an attenuated influenza virus is determined. In some embodiments, the effect of a Compound on the replication of a naturally occurring strain, variant or mutant of an influenza virus, a mutagenized influenza virus, a reassortant influenza virus and/or a genetically engineered influenza virus can be assessed. In a specific embodiment, the effect of a Compound on the replication of a vaccine strain of an influenza virus is determined.
  • the effect of a Compound on virus can be assessed using viral titer assays.
  • a monolayer of a target mammalian cell line is infected with different amounts (e.g. , multiplicity of 3 plaque forming units (pfu) or 5 pfu) of virus and subsequently cultured in the presence or absence of various dilutions of a Compound (e.g. , 0.1 ⁇ g/mL, 1 ⁇ g/mL, 5 ⁇ g/mL, or 10 ⁇ g/mL) to be tested.
  • a Compound e.g. 0.1 ⁇ g/mL, 1 ⁇ g/mL, 5 ⁇ g/mL, or 10 ⁇ g/mL
  • Infected cultures are harvested after a certain period of time (e.g., 48 hours or 72 hours) post infection and titered by standard plaque assays known in the art on the appropriate target cell line (e.g., Vero cell, MDCK cell, MBCK cell, human respiratory epithelial cell (e.g., A549 cells), HEK 293 cell, 293T cells, calf kidney cell or mink lung cell).
  • target cell line e.g., Vero cell, MDCK cell, MBCK cell, human respiratory epithelial cell (e.g., A549 cells), HEK 293 cell, 293T cells, calf kidney cell or mink lung cell.
  • culturing the infected cells in the presence of a Compound reduces the yield of infectious virus by at least 1.5 fold, 2, fold, 3, fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 25 fold, 30 fold, 35 fold, 40 fold, 45 fold, 50 fold, 100 fold, 500 fold, or 1000 fold relative to culturing the infected cells in the absence of Compounds.
  • Compound reduces the yield of infectious virus by at least 1 log, 1.5 logs, 2 logs, 2.5 logs, 3 logs, 3.5 logs, 4 logs, 4.5 logs, 5 logs, 6 logs, 7, logs, 8 logs, or 9 logs relative to culturing the infected cells in the absence of a Compound.
  • culturing the infected cells in the presence of a Compound reduces the yield of infectious virus by at least
  • culturing the infected cells in the presence of a Compound reduces the yield of infectious virus by 2 to 3, 2 to 4, 2 to 5, or 5 to 10 log relative to culturing the infected cells in the absence of the Compound. In another specific embodiment, culturing the infected cells in the presence of a Compound reduces the yield of infectious virus by at least
  • a virus is diluted into various concentrations and added to each well containing a monolayer of the target mammalian cells in triplicate. The plates are then incubated for a period of time to achieve effective infection of the control sample (e.g., 1 hour with shaking every fifteen minutes). After the incubation period, an equal amount of 1% agarose is added to an equal volume of each Compound dilution prepared in 2x concentration. In certain embodiments, Compounds at test concentrations between about 0.03 ⁇ g/ml to about 100 ⁇ g/ml can be tested with a final agarose overlay concentration of 0.5%.
  • the Compound-agarose mixture is applied to each well in 2 ml volume and the plates are incubated for three days, after which the cells are stained with a 1.5% solution of neutral red. At the end of the 4-6 hour incubation period, the neutral red solution is aspirated, and plaques counted using a stereomicroscope.
  • the plates are incubated for more than three days with additional overlays being applied on day four and on day 8 when appropriate.
  • the overlay medium is liquid rather than semi-solid.
  • Flow cytometry can be utilized to detect expression of virus antigens in infected target cells cultured in the presence or absence of Compounds (See, e.g., McSharry et al, Clinical Microbiology Rev., 1994, 7:576-604).
  • Non-limiting examples of viral antigens that can be detected on cell surfaces by flow cytometry include, but are not limited to HA of influenza.
  • intracellular viral antigens or viral nucleic acid can be detected by flow cytometry with techniques known in the art.
  • CPE is the morphological changes that cultured cells undergo upon being infected by most viruses. These morphological changes can be observed easily in unfixed, unstained cells by microscopy. Forms of CPE, which can vary depending on the virus, include, but are not limited to, rounding of the cells, appearance of inclusion bodies in the nucleus and/or cytoplasm of infected cells, and formation of syncytia, or polykaryocytes (large cytoplasmic masses that contain many nuclei).
  • the CPE assay can provide a measure of the effect of a Compound on virus replication.
  • Compounds are serially diluted (e.g. 1000, 500, 100, 50, 10, 1 ⁇ g/ml) and added to 3 wells containing a cell monolayer (preferably mammalian cells at 80-100% confluent) of a 96-well plate.
  • a cell monolayer preferably mammalian cells at 80-100% confluent
  • viruses are added and the plate sealed, incubated at 37°C for the standard time period required to induce near-maximal viral CPE (e.g., approximately 48 to 120 hours, depending on the virus and multiplicity of infection).
  • CPE When assaying a Compound for its potential activity, CPE is read microscopically after a known positive control drug (an antiviral) is evaluated in parallel with Compounds in each test.
  • a non-limiting example of a positive control is ribavirin for influenza.
  • the data is expressed as 50% effective concentrations or approximated virus- inhibitory concentration, 50% endpoint (IC 50 ) and cell-inhibitory concentration, 50% endpoint (CC 50 ).
  • IC 50 50% endpoint
  • CC 50 cell-inhibitory concentration
  • SI General selectivity index
  • a Compound has an SI of greater than 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 21, 22, 23, 24, 25, 30, 35, 39, 40, 45, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 1,000, or 10,000.
  • a Compound has an SI of greater than 10.
  • Compounds with an SI of greater than 10 are further assessed in other in vitro and in vivo assays described herein or others known in the art to characterize safety and efficacy. 5.2.3.1.5 Neutral Red NR Dye Uptake assay
  • the Neutral Red NR Dye Uptake assay can be used to validate the CPE inhibition assay.
  • the same 96-well microplates used for the CPE inhibition assay can be used.
  • Neutral red is added to the medium, and cells not damaged by virus take up a greater amount of dye.
  • the percentage of uptake indicating viable cells is read on a microplate autoreader at dual wavelengths of 405 and 540 nm, with the difference taken to eliminate background. (See McManus et ah, Appl. Environment. Microbiol. 31 :35- 38, 1976).
  • An EC 50 is determined for samples with infected cells and contacted with
  • Compounds, and an IC 50 is determined for samples with uninfected cells contacted with Compounds.
  • Lysed cells and supernatants from infected cultures such as those in the CPE assay can be used to assay for virus yield (production of viral particles after the primary infection).
  • these supernatants are serially diluted and added onto monolayers of susceptible cells (e.g., Vero cells). Development of CPE in these cells is an indication of the presence of infectious viruses in the supernatant.
  • the 90% effective concentration (EC 90 ) the Compound concentration that inhibits virus yield by 1 log, is determined from these data using known calculation methods in the art.
  • the EC 90 of a Compound is at least 1.5 fold, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 20 fold, 30 fold, 40 fold, or 50 fold less than the EC 90 of the negative control sample.
  • cells used in the antiviral assays described herein are susceptible to infection with a virus.
  • cell lines for use in antiviral assays are genetically engineered to render them more suitable hosts for viral infection or viral replication and more convenient substrates for rapidly detecting virus-infected cells (See, e.g., Olivo, P.D., Clin. Microbiol. Rev., 1996, 9:321-334).
  • Exemplary cell lines for use in assessing the ability of Compounds to inhibit influenza replication include, without limitation, Vero cells, 293T cells, and A549 cells.
  • Compounds and compositions are preferably assayed in vivo for the desired therapeutic or prophylactic activity prior to use in humans.
  • in vivo assays can be used to determine whether it is preferable to administer a Compound and/or another therapy.
  • the Compound can be administered before the animal is infected with the virus.
  • a Compound can be administered to the animal at the same time that the animal is infected with the virus.
  • the Compound is administered to animal after a viral infection.
  • a Compound is administered to the animal at the same time that the animal is infected with the virus to treat and/or manage the viral infection.
  • the Compound is administered to the animal more than one time.
  • Compounds can be tested for antiviral activity against virus in animal models systems including, but are not limited to, rats, mice, chicken, cows, monkeys, pigs, goats, sheep, dogs, rabbits, guinea pigs, etc.
  • Compounds are tested in a mouse model system. Such model systems are widely used and well-known to the skilled artisan.
  • Compounds can also be tested for replication enhancing activity toward virus replication in animal models systems including, but are not limited to, rats, mice, chicken, cows, monkeys, pigs, goats, sheep, dogs, rabbits, guinea pigs, etc.
  • Animals are infected with virus and concurrently or subsequently treated with a Compound or placebo. Alternatively, animals are treated with a Compound or placebo and subsequently infected with virus.
  • Samples obtained from these animals e.g., serum, urine, sputum, semen, saliva, plasma, or tissue sample
  • samples obtained from these animals can be tested for viral replication via well known methods in the art, e.g. , those that measure altered viral titers (as determined, e.g. , by plaque formation), the production of viral proteins (as determined, e.g., by Western blot, ELISA, or flow cytometry analysis) or the production of viral nucleic acids (as determined, e.g., by RT-PCR or northern blot analysis).
  • tissue samples are homogenized in phosphate-buffered saline (PBS), and dilutions of clarified homogenates are adsorbed for 1 hour at 37°C onto monolayers of cells (e.g., Vero, CEF or MDCK cells).
  • PBS phosphate-buffered saline
  • histopathologic evaluations are performed after infection, preferably evaluations of the organ(s) the virus is known to target for infection.
  • Virus immunohistochemistry can be performed using a viral-specific monoclonal antibody.
  • the effect of a Compound on a virus can also be determined using in vivo assays in which the titer of the virus in an infected subject administered a Compound, the length of survival of an infected subject administered a Compound, the immune response in an infected subject administered a Compound, the number, duration and/or severity of the symptoms in an infected subject administered a Compound, and/or the time period before onset of one or more symptoms in an infected subject administered a Compound is assessed. Techniques known to one of skill in the art can be used to measure such effects. [00158] Testing may be performed in normal animals, or in experimental virus disease models known in the art. For administration to animals, Compounds are formulated in a pharmaceutically acceptable carrier. Administration includes any suitable route of administration, such as parenteral, intraperitoneal, intravenous, pulmonary, intranasally, topically, and subcutaneous.
  • non-limiting examples of parameters that can be used to assay antiviral activity of a Compound administered to the influenza- infected mice include pneumonia-associated death, serum al- acid glycoprotein increase, animal weight, lung virus assayed by hemagglutinin, lung virus assayed by plaque assays, and histopathological change in the lung.
  • Statistical analysis is carried out to calculate significance ⁇ e.g., a P value of 0.05 or less).
  • Nasal turbinates and trachea may be examined for epithelial changes and subepithelial inflammation.
  • the lungs may be examined for bronchiolar epithelial changes and peribronchiolar inflammation in large, medium, and small or terminal bronchioles.
  • the alveoli are also evaluated for inflammatory changes.
  • the medium bronchioles are graded on a scale of 0 to 3+ as follows: 0 (normal: lined by medium to tall columnar epithelial cells with ciliated apical borders and basal pseudostratified nuclei; minimal inflammation); 1+
  • 2+ prominent changes in the epithelial layer ranging from attenuation to marked proliferation; cells disorganized and layer outline irregular at the luminal border
  • 3+ epitophelial layer markedly disrupted and disorganized with necrotic cells visible in the lumen; some bronchioles attenuated and others in marked reactive
  • the trachea is graded on a scale of 0 to 2.5+ as follows: 0 (normal: Lined by medium to tall columnar epithelial cells with ciliated apical border, nuclei basal and pseudostratified. Cytoplasm evident between apical border and nucleus. Occasional small focus with squamous cells); 1+ (focal squamous metaplasia of the epithelial layer); 2+ (diffuse squamous metaplasia of much of the epithelial layer, cilia may be evident focally); 2.5+ (diffuse squamous metaplasia with very few cilia evident).
  • Virus immunohistochemistry is performed using a viral-specific monoclonal antibody (e.g. NP-, N- or HN-specific monoclonal antibodies). Staining is graded 0 to 3+ as follows: 0 (no infected cells); 0.5+ (few infected cells); 1+ (few infected cells, as widely separated individual cells); 1.5+ (few infected cells, as widely separated singles and in small clusters); 2+ (moderate numbers of infected cells, usually affecting clusters of adjacent cells in portions of the epithelial layer lining bronchioles, or in small sublobular foci in alveoli); 3+ (numerous infected cells, affecting most of the epithelial layer in bronchioles, or widespread in large sublobular foci in alveoli).
  • a viral-specific monoclonal antibody e.g. NP-, N- or HN-specific monoclonal antibodies.
  • a Compound is assessed in human subjects infected with virus.
  • a Compound is administered to the human subject, and the effect of the Compound on viral replication can be measured by, e.g., analyzing the level of the virus or viral nucleic acids in a biological sample from the human subject (e.g., serum or plasma).
  • the effect of a Compound on viral replication can be assessed by comparing the level of virus replication in a subject or group of subjects treated with a control Compound to that in a subject or group of subjects treated with a Compound.
  • alterations in viral replication can be identified by comparing the level of the virus replication in a subject or group of subjects before and after the administration of a Compound. Techniques known to those of skill in the art can be used to obtain the biological sample and analyze the mRNA or protein expression.
  • the effect of a Compound on the severity of one or more symptoms associated with a virus infection/disease are assessed in an infected subject.
  • a Compound or a control Compound is administered to a human subject suffering from a virus infection and the effect of the Compound on one or more symptoms of the virus infection is determined.
  • the effect of a compound on the severity of one or more symptoms of a virus infection/disease can be determined by comparing the subjects treated with a control compound to the subjects treated with the Compound. Techniques known to physicians familiar with infectious diseases can be used to determine whether a Compound reduces one or more symptoms associated with the a viral disease.
  • the length of survival, frequency of hospitalization, and/or length of hospitalization of subjects with a virus infection/disease can be assessed. 5.2.4 Anticancer Assays
  • a Compound can be tested in vitro and/or in vivo for their ability to reduce the amount of cancer cells, or inhibit their proliferation.
  • the ability of a Compound to reduce the amount of cancer cells or inhibit their proliferation can be assessed by various approaches including, but not limited to: detecting the expression of antigens on cancer cells; detecting the proliferation or viability of cancer cells; and detecting the effector function of cancer cells. Techniques known to those skilled in the art can be used for measuring these activities. For example, cellular proliferation can be assayed by 3 H-thymidine incorporation assays and trypan blue cell counts.
  • Antigen expression can be assayed, for example, by immunoassays including, but not limited to, competitive and non-competitive assay systems using techniques such as Western blots, immunohistochemistry, radioimmunoassays, ELISA, "sandwich” immunoassays, immunoprecipitation assays, precipitin reactions, gel diffusion precipitin reactions, immunodiffusion assays, agglutination assays, complement-fixation assays, immunoradiometric assays, fluorescent immunoassays, protein A immunoassays, and FACS analysis.
  • immunoassays including, but not limited to, competitive and non-competitive assay systems using techniques such as Western blots, immunohistochemistry, radioimmunoassays, ELISA, "sandwich” immunoassays, immunoprecipitation assays, precipitin reactions, gel diffusion precipitin reactions, immunodiffusion assays, agglutination assays, complement-
  • a Compound is preferably tested in vitro and then in vivo for the desired therapeutic or prophylactic activity prior to use in humans.
  • assays which can be used to determine whether administration of a specific Compound is indicated include cell culture assays in which a patient tissue sample ⁇ e.g., cancer cells) is grown in culture and exposed to, or otherwise contacted with, a Compound, and the effect of such Compound upon the tissue sample is observed.
  • the tissue sample can be obtained by, e.g., biopsy from the patient.
  • a Compound can be tested in suitable animal model systems prior to use in humans for the treatment of cancer.
  • animal model systems include, but are not limited to, rats, mice, chicken, cows, monkeys, pigs, dogs, rabbits, etc. Any animal system well- known in the art may be used.
  • Several aspects of the procedure may vary; said aspects include, but are not limited to, the temporal regime of administering a Compound, whether such a Compound is administered separately or as an admixture, and the frequency of administration of the Compound.
  • Animal models for cancer can be used to assess the efficacy of a Compound or a combination therapy described herein.
  • animal models for lung cancer include, but are not limited to, lung cancer animal models described by Zhang & Roth (1994, In Vivo 8(5):755-69) and a transgenic mouse model with disrupted p53 function (see, e.g., Morris et al. J. La. State Med. Soc. 1998, 150(4): 179-85).
  • An example of an animal model for breast cancer includes, but is not limited to, a transgenic mouse that overexpresses cyclin Dl (see, e.g., Hosokawa et al., Transgenic Res. 2001, 10(5), 471-8.
  • An example of an animal model for colon cancer includes, but is not limited to, a TCR b and p53 double knockout mouse (see, e.g., Kado et al., Cancer Res. 2001, 61(6):2395-8).
  • animal models for pancreatic cancer include, but are not limited to, a metastatic model of Panc02 murine pancreatic adenocarcinoma (see, e.g., Wang et al., Int. J. Pancreatol. 2001, 29(l):37-46) and nu-nu mice generated in subcutaneous pancreatic tumours (see, e.g., Ghaneh et al., Gene Ther. 2001, 8(3): 199-208).
  • Examples of animal models for non-Hodgkin's lymphoma include, but are not limited to, a severe combined immunodeficiency ("SOD") mouse (see, e.g., Bryant et al., Lab Invest. 2000, 80(4), 553-73) and an IgHmu-HOXl 1 transgenic mouse (see, e.g., Hough et al, Proc. Natl. Acad. Sci. U.S.A. 1998, 95(23), 13853-8.
  • SOD severe combined immunodeficiency
  • IgHmu-HOXl 1 transgenic mouse see, e.g., Hough et al, Proc. Natl. Acad. Sci. U.S.A. 1998, 95(23), 13853-8.
  • an animal model for esophageal cancer includes, but is not limited to, a mouse transgenic for the human papillomavirus type 16 E7 oncogene (see, e.g., Herber et al., J. Virol. 1996, 70(3): 1873-81).
  • animal models for colorectal carcinomas include, but are not limited to, Ape mouse models (see, e.g., Fodde & Smits, Trends Mol. Med. 2001, 7(8):369- 73 and Kuraguchi et al., Oncogene 2000, 19(50), 5755-63).
  • an imaging agent or diagnostic moiety, which binds to molecules on cancer cells, e.g., cancer cell surface antigens.
  • a fluorescent tag, radionuclide, heavy metal, or photon-emitter is attached to an antibody (including an antibody fragment) that binds to a cancer cell surface antigen.
  • the medical practitioner can infuse the labeled antibody into the patient either prior to, during, or following treatment with a Compound, and then the practitioner can place the patient into a total body scanner/developer which can detect the attached label ⁇ e.g., fluorescent tag, radionuclide, heavy metal, photon-emitter).
  • the scanner/developer e.g., CT, MRI, or other scanner, e.g. detector of fluorescent label, that can detect the label
  • the mapping and quantitation of tag e.g. fluorescence, radioactivity, etc.
  • tag e.g. fluorescence, radioactivity, etc.
  • a reference control such as the same patient at an earlier time point or a patient who has no detectable cancer.
  • a large signal relative to a reference range or a prior treatment date, or prior to treatment
  • a signal decrease indicates that therapy has been effective.
  • the efficacy of the therapeutic regimen in reducing the amount of cancer cells in animals (including humans) undergoing treatment can be evaluated using in vivo techniques.
  • the medical practitioner performs the imaging technique with labeled molecule that specifically binds the surface of a cancer cell.
  • the mapping and quantitation of tag ⁇ e.g., fluorescence, radioactivity) in patterns within a tissue or tissues indicates the treatment efficacy within the body of the patient undergoing treatment.
  • compositions comprising an effective amount of a Compound and compositions comprising an effective amount of a Compound and a pharmaceutically acceptable carrier or vehicle, wherein a pharmaceutically acceptable carrier or vehicle can comprise an excipient, diluent, or a mixture thereof.
  • the composition is a pharmaceutical composition.
  • a pharmaceutical composition described herein is suitable for oral, pulmonary, parenteral, mucosal, transdermal or topical
  • a Compound or composition thereof can also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously,
  • the mode of administration is left to the discretion of the health-care practitioner, and can depend in-part upon the site of the medical condition.
  • the Compounds can be administered to a patient orally or parenterally in the conventional form of preparations, such as capsules, microcapsules, tablets, granules, powder, troches, pills, suppositories, injections, suspensions and syrups.
  • Suitable formulations can be prepared by methods commonly employed using conventional, organic or inorganic additives, such as an excipient (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), a binder (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose or starch), a disintegrator (e.g., starch, carboxymethylcellulose, hydroxypropylstarch, low substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate or calcium citrate), a lubricant (e.g., magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate), a flavoring agent (e.g., citric acid, menthol, glycine), a
  • the effective amount of the Compound in the pharmaceutical composition may be at a level that will exercise the desired effect.
  • the effective amount of a Compound in a pharmaceutical composition is about 0.005 mg/kg of a patient's body weight to about 10 mg/kg of a patient's body weight in unit dosage for both oral and parenteral administration.
  • Compound in a pharmaceutical composition is about 0.005 mg/kg of a patient's body weight to about 50 mg/kg of a patient's body weight in unit dosage for both oral and parenteral administration.
  • the effective amount of a Compound in a pharmaceutical composition is about 0.005 mg/kg of a patient's body weight to about 100 mg/kg of a patient's body weight in unit dosage for both oral and parenteral administration.
  • a Compound or composition thereof can be administered once, twice, three, four or more times daily.
  • a Compound or composition thereof can be administered orally for reasons of convenience.
  • a Compound or composition thereof when administered orally, a Compound or composition thereof is administered with a meal and water.
  • the Compound is dispersed in water or juice (e.g., apple juice or orange juice) and administered orally as a suspension.
  • a Compound when administered orally, a Compound is administered to a subject in a fasted state.
  • compositions comprising Compounds can be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, troches, suppositories and suspensions and the like.
  • Compositions can be formulated to contain a daily dose, or a convenient fraction of a daily dose, in a dosage unit, which may be a single tablet or capsule or convenient volume of a liquid.
  • the solutions are prepared from water-soluble salts, such as the hydrochloride salt.
  • all of the compositions are prepared according to known methods in pharmaceutical chemistry.
  • Capsules can be prepared by mixing a Compound with a suitable carrier or diluent and filling the proper amount of the mixture in capsules.
  • suitable carriers and diluents include, but are not limited to, inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.
  • Tablets can be prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants and disintegrators as well as the Compound.
  • Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful.
  • the pharmaceutical composition is lactose-free.
  • Typical tablet binders are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.
  • a lubricant might be necessary in a tablet formulation to prevent the tablet and punches from sticking in the die.
  • the lubricant can be chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.
  • Tablet disintegrators are substances that swell when wetted to break up the tablet and release the Compound. They include starches, clays, celluloses, algins and gums. More particularly, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose, for example, can be used as well as sodium lauryl sulfate. Tablets can be coated with sugar as a flavor and sealant, or with film- forming protecting agents to modify the dissolution properties of the tablet.
  • the compositions can also be formulated as chewable tablets, for example, by using substances such as mannitol in the
  • Cocoa butter is a traditional suppository base, which can be modified by addition of waxes to raise its melting point slightly.
  • Water-miscible suppository bases comprising, particularly, polyethylene glycols of various molecular weights are in wide use.
  • a slowly soluble pellet of the Compound can be prepared and incorporated in a tablet or capsule, or as a slow-release implantable device.
  • the technique also includes making pellets of several different dissolution rates and filling capsules with a mixture of the pellets. Tablets or capsules can be coated with a film that resists dissolution for a predictable period of time.
  • the parenteral preparations can be made long-acting, by dissolving or suspending the Compound in oily or emulsified vehicles that allow it to disperse slowly in the serum.
  • provided herein are capsules containing a Compound without an additional carrier, excipient or vehicle.
  • the methods for treating an interferon-sensitive disease involve the administration of a Compound, as a single-agent therapy, to a patient in need thereof.
  • a method for treating an interferon-sensitive disease comprising administering to a patient in need thereof an effective amount of a Compound, as a single agent.
  • a method for treating an interferon- sensitive disease comprising administering to a patient in need thereof a pharmaceutical composition comprising a Compound, as the single active ingredient, and a pharmaceutically acceptable carrier, excipient or vehicle.
  • a Compound e.g., a compound of formula I, II, III, IV, or V.
  • the methods for treating an interferon-sensitive disease involve the administration of a Compound in combination with another therapy (e.g., one or more additional therapies that do not comprise a Compound, and/or that comprise a different Compound) to a patient in need thereof.
  • another therapy e.g., one or more additional therapies that do not comprise a Compound, and/or that comprise a different Compound
  • Such methods may involve administering a
  • Such methods have an additive or synergistic effect.
  • presented herein is a method for treating an interferon-sensitive disease, comprising administering to a patient in need thereof an effective amount of a Compound and an effective amount of another therapy.
  • the methods for treating an interferon-sensitive disease provided herein increase the survival of a patient diagnosed with an interferon-sensitive disease.
  • the methods for treating an interferon-sensitive disease provided herein reduce the mortality of subjects diagnosed with an interferon-sensitive disease.
  • the methods for treating an interferon-sensitive disease provided herein increase symptom- free survival of an interferon-sensitive disease patients.
  • the methods for treating an interferon-sensitive disease provided herein do not cure an interferon-sensitive disease in patients, but prevent the progression or worsening of the disease.
  • the methods for treating an interferon-sensitive disease provided herein enhance or improve the therapeutic effect of another therapy.
  • the methods for treating an interferon-sensitive disease provided herein prevent the onset or development of an interferon-sensitive disease.
  • the methods for treating an interferon-sensitive disease provided herein provided herein decrease the requirement for hospitalization. In certain embodiments, the methods for treating an interferon-sensitive disease provided herein provided herein decrease the length and/or frequency of hospitalization.
  • the methods for treating an interferon-sensitive disease provided herein reduce hospitalization (e.g., the frequency or duration of hospitalization) of a patient diagnosed with an interferon-sensitive disease. In some embodiments, the methods for treating an interferon-sensitive disease provided herein reduce hospitalization length of a patient diagnosed with an interferon-sensitive disease. In certain embodiments, the methods for treating an interferon-sensitive disease provided herein decrease the hospitalization rate.
  • hospitalization e.g., the frequency or duration of hospitalization
  • the methods for treating an interferon-sensitive disease provided herein provided herein result in one or more of the following: (i) reduction or prevention of the recurrence of the disease; (ii) reduction of the duration of the disease; (iii) prevention or reduction of organ failure associated with the disease; (iv) elimination or curing of the disease; and/or (v) an improvement in the general quality of life as assessed by, e.g., questionnaire.
  • the methods for treating an interferon-sensitive disease provided herein alleviate or manage one, two or more symptoms associated with an interferon-sensitive disease. Alleviating or managing one, two or more symptoms of an interferon-sensitive disease may be used as a clinical endpoint for efficacy of a Compound for treating an interferon-sensitive disease. In some embodiments, the methods for treating an interferon-sensitive disease provided herein reduce the duration and/or severity of one or more symptoms associated with an interferon-sensitive disease. In some embodiments, the methods for treating an interferon-sensitive disease provided herein prevent or inhibit the onset, progression and/or recurrence of one or more symptoms associated with an interferon- sensitive disease.
  • the methods for treating an interferon-sensitive disease provided herein reduce the number of symptoms associated with an interferon- sensitive disease. In certain embodiments, the methods for treating an interferon-sensitive disease provided herein inhibit or reduce the progression of one or more symptoms associated therewith.
  • a Compound or a composition thereof used in a method for treating an interferon- sensitive disease may be used as any line of therapy (e.g., a first, second, third, fourth or fifth line therapy).
  • the methods for treating an interferon-sensitive disease comprise administration of a Compound in an amount sufficient to treat the interferon- sensitive disease.
  • the Compounds, compositions, and pharmaceutical compositions are used in an amount that is not
  • Methods of testing toxicity include any method known in the art, for example, as described supra and in Section 5.2.2 above.
  • the choice of Compounds to be used depends on a number of factors, including but not limited to the type of interferon-sensitive disease, health and age of the patient, and toxicity or side effects.
  • the interferon-sensitive disease treated in accordance with the methods provided herein is a viral disease (i.e., a disease caused by a virus).
  • the viral disease can be caused by an orthomyxovirus (e.g., influenza virus), Adenovirus, arbovirus, paramyxovirus, baculovirus, coronavirus, papillomavirus, parvovirus, chickenpox virus, reovirus, Ebola virus, Ebola-like virus, echo virus, encephalitis virus, filovirus, hantavirus, hepatitis virus, German measles virus, cytomegalovirus, hemorrhagic fever virus, herpes simplex virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, human immunodeficiency virus (HIV), human papillomavirus (the causative agent of genital warts), human T cell leukemia virus, human T cell lymph
  • Newcastle disease virus oncornavirus, orbivirus, parainfluenza virus, paramyxovirus, parvovirus, picornavirus, rabies virus, respiratory syncytial virus, rhinovirus, rubella virus, rubeola virus, SARS virus, Sendai virus, simian immunodeficiency virus, simian
  • the Compound used to treat a viral disease is Compound I.
  • the Compound used to treat a viral disease is Compound 13, 26, 27, and/or 28.
  • the Compound used to treat a viral disease is Compound 12, 14, 15, 16, 18, 19, 20, and/or 29.
  • the methods for treating a viral disease with a Compound result in one or more of the following: (i) reduction or prevention of the spread of a virus from one cell to another cell, one tissue to another tissue, or one organ to another organ; (ii) reduction or prevention of the spread of a virus from one subject to another subject; (iii) inhibition or reduction of viral replication; (iv) inhibition or reduction of the entry of a virus into a host cell(s); (v) inhibition or reduction of replication of the viral genome; (vi) inhibition or reduction of synthesis of viral proteins; (vii) inhibition or reduction of assembly of viral particles; (viii) inhibition or reduction of release of viral particles from a host cell(s); and/or (ix) reduction of viral titer.
  • the methods for treating a viral disease provided herein reduce or eliminate one, two, or more symptoms associated with the viral disease.
  • the interferon-sensitive disease is influenza virus disease.
  • Symptoms of influenza virus disease include, but are not limited to, body aches (especially joints and throat), fever, nausea, headaches, irritated eyes, fatigue, sore throat, reddened eyes or skin, and abdominal pain.
  • the Compound used to treat influenza virus disease is Compound 1.
  • the Compound used to treat influenza virus disease is Compound 13, 26, 27, and/or 28.
  • the Compound used to treat influenza virus disease is Compound 12, 14, 15, 16, 18, 19, 20, and/or 29.
  • the methods for treating influenza virus disease provided herein reduce or eliminate one, two, or more of the following: body aches (especially joints and throat), fever, nausea, headaches, irritated eyes, fatigue, sore throat, reddened eyes or skin, and abdominal pain.
  • the methods for treating influenza virus disease provided herein inhibit or reduce replication of the influenza virus. In certain embodiments, the methods for treating influenza virus disease provided herein inhibit or reduce replication of the influenza viral genome, inhibit or reduce the production of viral proteins, and/or reduce viral titers.
  • the interferon-sensitive disease treated in accordance with the methods provided herein is a viral infection.
  • a method of treating a virus infection or a symptom associated therewith in a subject comprising administering to a subject in need thereof an effective amount of a Compound.
  • the Compound used to treat a viral infection is Compound I.
  • the Compound used to treat a viral infection is Compound 13, 26, 27, and/or 28.
  • the Compound used to treat a viral infection is Compound 12, 14, 15, 16, 18, 19, 20, and/or 29.
  • the methods of treating a viral infection prevent the progression of the infection and/or the onset of disease caused by the viral infection.
  • a method for preventing the progression of a viral infection and/or the onset of disease caused by the viral infection comprises administering an effective amount of a Compound to a subject in need thereof.
  • the methods of treating a viral infection prevent the onset, progression and/or recurrence of a symptom associated with a viral infection.
  • a method for preventing a symptom associated with a viral infection in a subject comprises administering an effective amount of a
  • the interferon-sensitive disease treated in accordance with the methods provided herein is a viral infection, wherein the viral infection is an orthomyxovirus infection.
  • the Compound used to treat an orthomyxovirus infection is Compound 1.
  • the Compound used to treat an orthomyxovirus infection is Compound 13, 26, 27, and/or 28.
  • the Compound used to treat an orthomyxovirus infection is Compound 12, 14, 15, 16, 18, 19, 20, and/or 29.
  • the methods of treating an orthomyxovirus infection prevent the progression of the infection and/or the onset of disease caused by the orthomyxovirus infection.
  • a method for preventing the progression of an orthomyxovirus infection and/or the onset of disease caused by the orthomyxovirus infection comprises administering an effective amount of a
  • a method for preventing a symptom associated with an orthomyxovirus infection in a subject comprises administering an effective amount of a Compound to a subject in need thereof.
  • the interferon-sensitive disease treated in accordance with the methods provided herein is a viral infection, wherein the viral infection is an influenza virus infection.
  • the Compound used to treat an influenza virus infection or a symptom associated therewith is Compound 1.
  • the Compound used to treat an influenza virus infection or a symptom associated therewith is Compound 13, 26, 27, and/or 28.
  • the Compound used to treat an influenza virus infection or a symptom associated therewith is Compound 12, 14, 15, 16, 18, 19, 20, and/or 29.
  • the methods of treating an influenza virus infection prevent the progression of the infection and/or the onset of disease caused by the influenza virus infection.
  • a method for preventing the progression of an influenza virus infection and/or the onset of disease caused by the influenza virus infection comprises administering an effective amount of a Compound to a subject in need thereof.
  • the methods of treating an influenza virus infection prevent the onset, progression and/or recurrence of a symptom associated with an influenza infection.
  • a method for preventing a symptom associated with an influenza virus infection in a subject comprises administering an effective amount of a Compound to a subject in need thereof.
  • the interferon-sensitive disease treated in accordance with the methods provided herein is a viral infection, wherein the viral infection is an influenza A, influenza B, or influenza C virus infection.
  • the influenza virus is any type, subtype, and/or strain of influenza A virus.
  • influenza virus is a particular type, subtype, and/or strain of influenza virus.
  • the Compound used to treat an influenza A, influenza B, or influenza C virus infection is Compound 1.
  • Compound 1 is used to treat an H1N1, H3N2, and/or H5N1 influenza virus.
  • the Compound used to treat an influenza A, influenza B, or influenza C virus infection is Compound 13, 26, 27, and/or 28.
  • the Compound used to treat an influenza A, influenza B, or influenza C virus infection is Compound 12, 14, 15, 16, 18, 19, 20, and/or 29.
  • the interferon-sensitive disease treated in accordance with the methods provided herein is a viral infection, wherein the viral infection is a vesicular stomatitis virus infection.
  • the Compound used to treat a vesicular stomatitis virus infection or a symptom associated therewith is Compound 13, 26, 27, and/or 28.
  • the Compound used to treat a vesicular stomatitis virus infection or a symptom associated therewith is Compound 12, 14, 15, 16, 18, 19, 20, and/or 29.
  • the interferon-sensitive disease treated in accordance with the methods provided herein is a viral infection, wherein the viral infection is a hepatitis virus (e.g., hepatitis B or hepatitis C) infection.
  • the Compound used to treat a hepatitis virus (e.g., hepatitis B or hepatitis C) infection is
  • the Compound used to treat a hepatitis virus (e.g., hepatitis B or hepatitis C) infection is Compound 12, 14, 15, 16, 18, 19, 20, and/or 29.
  • the interferon-sensitive disease treated in accordance with the methods provided herein is a viral infection, wherein the viral infection is a retrovirus infection.
  • the Compound used to treat a retrovirus infection is Compound 13, 26, 27, and/or 28.
  • the Compound used to treat a retrovirus infection is Compound 12, 14, 15, 16, 18, 19, 20, and/or 29.
  • the interferon-sensitive disease treated in accordance with the methods provided herein is a viral infection, wherein the viral infection is a human immunodeficiency virus (HIV) infection.
  • HIV human immunodeficiency virus
  • Compound used to treat a HIV infection is Compound 13, 26, 27, and/or 28.
  • the Compound used to treat a HIV infection is Compound 12, 14, 15, 16, 18, 19, 20, and/or 29.
  • the interferon-sensitive disease treated in accordance with the methods provided herein is a viral infection, wherein the viral infection is not a retrovirus infection.
  • the interferon-sensitive disease treated in accordance with the methods provided herein is a viral infection, wherein the viral infection is not a HIV infection.
  • the interferon-sensitive disease treated in accordance with the methods provided herein is a viral infection, wherein the viral infection is not a hepatitis virus infection.
  • the interferon-sensitive disease treated in accordance with the methods provided herein is not a virus infection.
  • the interferon-sensitive disease treated in accordance with the methods provided herein is a viral infection, wherein the Compound used in the method is not Compound 9.
  • the interferon-sensitive disease treated in accordance with the methods provided herein is an HIV infection, wherein the Compound used in the method is not Compound 4.
  • the interferon- sensitive disease treated in accordance with the methods provided herein is an HIV infection, wherein the Compound used in the method is not Compound 7.
  • the interferon-sensitive disease treated in accordance with the methods provided herein is an HIV infection, wherein the Compound used in the method is not Compound 10.
  • the subject with a viral infection being treated with a Compound does not have cancer.
  • the interferon-sensitive disease treated in accordance with the methods provided herein is cancer.
  • Symptoms of cancer include, but are not limited to, persistent cough or blood-tinged saliva, blood in the stool, anemia, localized pain, blood in the urine, hoarseness, swollen glands, swollen lymph nodes, fever, fatigue, indigestion, difficulty swallowing, reduction in leukocytes, weight loss, itching, sore, headaches, and back pain.
  • the Compound used to treat cancer is Compound 11, 13, 14, 15, 16, 22, 23, 25, 26, 27, and/or 28.
  • the methods for treating cancer provided herein reduce or eliminate one, two, or more of the following: persistent cough or blood-tinged saliva, blood in the stool, anemia, localized pain, blood in the urine, hoarseness, swollen glands, swollen lymph nodes, fever, fatigue, indigestion, difficulty swallowing, reduction in leukocytes, weight loss, itching, sore, headaches, and back pain.
  • the methods for treating cancer with a Compound result in one or more of the following: (i) reduction or inhibition of the replication of cancer cells; (ii) an impairment in the formation of a tumor; (iii) eradication, removal, or control of primary, regional and/or metastatic cancer; (iv) the size of a tumor is maintained and does not increase or increases by less than 10%, preferably less than 5%, preferably less than 4%, preferably less than 2% as determined by, e.g., radiology or MRI; (v) an increase in the number of patients in remission from cancer; (vi) a stabilization, reduction or elimination in the cancer cell population; (vii) stabilization or reduction in the growth of a tumor or neoplasm; (viii) a decrease in the need for chemotherapy and/or radiation treatment; (ix) a reduction in hospitalization rate and/or length; (x) an increase in survival; and/or (xi) an increase in cancer-free survival.
  • the interferon-sensitive disease treated in accordance with the methods provided herein is a hematologic cancer.
  • the Compound used to treat the hematologic cancer is Compound 11, 13, 14, 15, 16, 22, 23, 25, 26, 27, and/or 28.
  • the interferon-sensitive disease treated in accordance with the methods provided herein is cancer, wherein the cancer the cancer is hairy cell leukemia, chronic myeloid leukemia, nodular lymphoma, cutaneous T-cell lymphoma, papilloma, cutaneous melanoma, or basal cell carcinoma.
  • the Compound used to treat hairy cell leukemia, chronic myeloid leukemia, nodular lymphoma, cutaneous T-cell lymphoma, papilloma, cutaneous melanoma, or basal cell carcinoma is Compound 11, 13, 14, 15, 16, 22, 23, 25, 26, 27, and/or 28.
  • the interferon-sensitive disease treated in accordance with the methods provided herein a non-hematologic cancer.
  • the Compound used to treat the non-hematologic cancer is Compound 11, 13, 14, 15, 16, 22, 23, 25, 26, 27, and/or 28.
  • the interferon-sensitive disease treated in accordance with the methods provided herein is cancer, wherein the cancer is not hairy cell leukemia, chronic myeloid leukemia, nodular lymphoma, cutaneous T-cell lymphoma, papilloma, cutaneous melanoma, or basal cell carcinoma.
  • the interferon-sensitive disease treated in accordance with the methods provided herein is not cancer.
  • the interferon-sensitive disease treated in accordance with the methods provided herein is cancer, wherein the Compound used in the method is not Compound 4.
  • the interferon-sensitive disease treated in accordance with the methods provided herein is cancer, wherein the Compound used in the method is not Compound 5.
  • the interferon-sensitive disease treated in accordance with the methods provided herein is cancer, wherein the Compound used in the method is not Compound 6.
  • the interferon-sensitive disease treated in accordance with the methods provided herein is cancer, wherein the Compound used in the method is not Compound 7.
  • the interferon-sensitive disease treated in accordance with the methods provided herein is cancer, wherein the Compound used in the method is not Compound 9.
  • the interferon-sensitive disease treated in accordance with the methods provided herein is cancer, wherein the Compound used in the method is not Compound 10.
  • the interferon-sensitive disease treated in accordance with the methods provided herein is an autoimmune disease.
  • the Compound used to treat an autoimmune disease is Compound 11, 13, 14, 15, 16, 22, 23, 25, 26, 27, and/or 28.
  • the Compound used to treat the autoimmune disease is Compound 5, 6, 7, 9, and/or 10.
  • the subject with an autoimmune disease being treated with a Compound does not have cancer.
  • the interferon-sensitive disease treated in accordance with the methods provided herein is an autoimmune disease, wherein the autoimmune disease is multiple sclerosis.
  • Symptoms of multiple sclerosis include, but are not limited to, loss of balance, numbness or abnormal sensation in any area, pain associated with muscle spasms, pain in the arms or legs, problems moving arms or legs, problems walking, problems with coordination and making small movements, slurred or difficult-to-understand speech, tremor in one or more arms or legs, uncontrollable spasm of muscle groups (muscle spasticity), weakness in one or more arms or legs, double vision, eye discomfort, uncontrollable rapid eye movements, vision loss, decreased attention span, decreased judgment, decreased memory, depression or feelings of sadness, dizziness, facial pain, hearing loss, fatigue, constipation, difficulty beginning urinating, frequent need to urinate, stool leakage, strong urge to urinate, and urine leakage (incontinence).
  • the Compound used to treat multiple sclerosis is Compound 11, 13, 14, 15, 16, 22, 23, 25, 26, 27, and/or 28. In another specific embodiment, the Compound used to treat multiple sclerosis is Compound 5, 6, 7, 9, and/or 10. In certain embodiments, the subject with multiple sclerosis being treated with a Compound does not have cancer.
  • the methods for treating multiple sclerosis reduce or eliminate one, two, or more of the following: loss of balance, numbness or abnormal sensation in any area, pain associated with muscle spasms, pain in the arms or legs, problems moving arms or legs, problems walking, problems with coordination and making small movements, slurred or difficult-to-understand speech, tremor in one or more arms or legs, uncontrollable spasm of muscle groups (muscle spasticity), weakness in one or more arms or legs, double vision, eye discomfort, uncontrollable rapid eye movements, vision loss, decreased attention span, decreased judgment, decreased memory, depression or feelings of sadness, dizziness, facial pain, hearing loss, fatigue, constipation, difficulty beginning urinating, frequent need to urinate, stool leakage, strong urge to urinate, and urine leakage (incontinence).
  • the interferon-sensitive disease treated in accordance with the methods provided herein is an autoimmune disease, wherein the autoimmune disease is not multiple sclerosis. In certain embodiments, the interferon-sensitive disease treated in accordance with the methods provided herein is not an autoimmune disease.
  • a subject with an interferon-sensitive disease is treated with a Compound, wherein the interferon-sensitive disease is a bacterial infection or a disease caused by bacteria.
  • Symptoms of bacterial infections include, but are not limited to, localized redness, localized heat, localized, swelling, localized pain, fatigue, dizziness, fever, discharge in the infected area, and general body aches/pain.
  • the Compound used to treat a bacterial infection or a disease caused by bacteria is Compound 11, 13, 14, 15, 16, 22, 23, 25, 26, 27, and/or 28.
  • the Compound used to treat a bacterial infection or a disease caused by bacteria is Compound 5, 6, 7, 9, and/or 10.
  • the methods of treating a bacterial infection prevent the progress of the infection and/or the onset of a disease caused by the bacterial infection.
  • a method for preventing the progression of a bacterial infection and/or the onset of disease caused by the bacterial infection comprises administering an effective amount of a Compound to a subject in need thereof.
  • the methods of treating a bacterial infection prevent the onset, progression and/or recurrence of a symptom associated with a bacterial infection.
  • a method for preventing a symptom associated with a bacteria infection in a subject comprises administering an effective amount of a Compound to a subject in need thereof.
  • the subject with a bacterial infection being treated with a Compound does not have cancer.
  • the methods for treating a bacterial infection reduce or eliminate one, two, or more of the following: localized redness, localized heat, localized, swelling, localized pain, fatigue, dizziness, fever, discharge in the infected area, and/or general body aches/pain.
  • Also provided herein are methods for enhancing the immune response in a subject to a vaccine e.g., a live virus vaccine or an inactivated virus vaccine
  • a vaccine e.g., a live virus vaccine or an inactivated virus vaccine
  • a Compound modulates the effect of the vaccine, e.g., the Compound increases the efficacy of the vaccine.
  • a Compound administered with a vaccine can be administered prior to, concurrently with, or subsequent to the administration of the vaccine.
  • the vaccine is a live virus vaccine or other type of attenuated vaccine.
  • the vaccine is an inactivated virus vaccine or subunit vaccine.
  • the Compound used to enhance the immune response in a subject is Compound I.
  • the Compound used to enhance the immune response in a subject is Compound 13, 26, 27, and/or 28.
  • the compositionpound 13, 26, 27, and/or 28 is another specific embodiment, the
  • Compound used to enhance the immune response in a subject is Compound 12, 14, 15, 16, 18, 19, 20, and/or 29.
  • a subject treated for an interferon-sensitive disease in accordance with the methods provided herein is an animal (e.g., a human or non-human animal) that has or is diagnosed with an interferon-sensitive disease.
  • a subject treated for an interferon-sensitive disease in accordance with the methods provided herein is an animal (e.g., a human or non-human animal) predisposed or susceptible to an interferon-sensitive disease.
  • a subject treated for an interferon- sensitive disease in accordance with the methods provided herein is an animal (e.g., a human or non-human animal) at risk of developing an interferon-sensitive disease.
  • a Compound is administered to a subject that is to receive a vaccine, i.e., a Compound is used as an adjuvant.
  • the subject receiving the vaccine has an interferon-sensitive disease.
  • the subject receiving the vaccine is at risk of developing an interferon-sensitive disease.
  • the subject receiving the vaccine does not have an interferon- sensitive disease.
  • a Compound is administered to a subject that has received a vaccine.
  • the subject that received the vaccine has an interferon-sensitive disease.
  • the subject that received the vaccine is at risk of developing an interferon-sensitive disease.
  • the subject that received the vaccine does not have an interferon-sensitive disease.
  • a subject treated for an interferon-sensitive disease or administered a Compound as an adjuvant in accordance with the methods provided herein is a human infant.
  • a subject treated for an interferon-sensitive disease or administered a Compound as an adjuvant in accordance with the methods provided herein is a premature human infant.
  • a subject treated for an interferon-sensitive disease or administered a Compound as an adjuvant in accordance with the methods provided herein is a human toddler.
  • a subject treated for an interferon- sensitive disease or administered a Compound as an adjuvant in accordance with the methods provided herein is a human child.
  • a subject treated for an interferon- sensitive disease or administered a Compound as an adjuvant in accordance with the methods provided herein is a human adult.
  • a subject treated for an interferon- sensitive disease or administered a Compound as an adjuvant in accordance with the methods provided herein is a middle-aged human (e.g., a human aged 30-65 years old).
  • Compound as an adjuvant in accordance with the methods provided herein is an elderly human.
  • Compound I is administered to patients receiving or that have received a viral vaccine.
  • Compound I is administered to patients receiving or that have received a viral vaccine, wherein the viral vaccine comprises live, attenuated virus.
  • the viral vaccine is influenza vaccine.
  • the viral vaccine is respiratory syncytial virus (RSV) vaccine.
  • the viral vaccine is a rotavirus vaccine, MMR vaccine, yellow fever vaccine, or varicella virus vaccine (e.g., a vaccine for chicken pox or shingles).
  • Compound II is administered to patients receiving or that have received a viral vaccine.
  • Compound II is administered to patients receiving or that have received a live viral vaccine. In certain embodiments, Compound II is administered to patients receiving or that have received an inactivated viral vaccine. In certain embodiments, Compound II is administered to patients receiving or that have received an influenza virus vaccine. In certain embodiments, Compound II is administered to patients receiving or that have received an RSV vaccine. In other words,
  • Compound II is administered to patients receiving or that have received a vaccine, wherein the vaccine is not a viral vaccine. In certain embodiments, Compound II is administered to patients receiving or that have received a cancer vaccine.
  • a subject treated for an interferon-sensitive disease or administered a Compound as an adjuvant in accordance with the methods provided herein is a human that is about 1 to about 5 years old, about 5 to 10 years old, about 10 to about 18 years old, about 18 to about 30 years old, about 25 to about 35 years old, about 35 to about 45 years old, about 40 to about 55 years old, about 50 to about 65 years old, about 60 to about 75 years old, about 70 to about 85 years old, about 80 to about 90 years old, about 90 to about 95 years old or about 95 to about 100 years old, or any age in between.
  • a subject treated for an interferon-sensitive disease or administered a Compound an adjuvant in accordance with the methods provided herein is a human that is 18 years old or older.
  • a subject treated for an interferon-sensitive disease or administered a Compound as an adjuvant in accordance with the methods provided herein is a human that is between the age of 12 years old and 18 years old.
  • the subject is a male human.
  • the subject is a female human.
  • the subject is a female human that is not pregnant or is not breastfeeding.
  • the subject is a female that is pregnant or will/might become pregnant, or is breast feeding.
  • a subject treated for an interferon-sensitive disease or administered a Compound as an adjuvant in accordance with the methods provided herein is a human that is in an immunocompromised state or immunosuppressed state.
  • Compound as an adjuvant in accordance with the methods provided herein is a human receiving or recovering from immunosuppressive therapy.
  • a subject treated for an interferon-sensitive disease or administered a Compound as an adjuvant in accordance with the methods provided herein is a human that has or is at risk of getting cancer (e.g., metastatic cancer), or at risk of being infected by a pathogen.
  • Compound as an adjuvant in accordance with the methods provided herein is a human that has or is at risk of being infected by a virus.
  • a subject treated for an interferon-sensitive disease or administered a Compound as an adjuvant in accordance with the methods provided herein is a human that has or is at risk of being infected by an influenza virus.
  • a subject treated for an interferon-sensitive disease or administered a Compound as an adjuvant in accordance with the methods provided herein is a human that has or is at risk of being infected by a bacteria.
  • Compound as an adjuvant in accordance with the methods provided herein is a human who is, will, or has undergone surgery, drug therapy, such as chemotherapy, hormonal therapy and/or radiation therapy.
  • a subject treated for an interferon-sensitive disease in accordance with the methods provided herein is suffering from a condition wherein the administration of therapies other than Compounds may be contraindicated.
  • the subject to be treated is severely ill. In some embodiments, the subject to be treated is severely ill.
  • the subject to be treated is unresponsive, or poorly responsive, to one or more previous therapies.
  • a subject treated for an interferon-sensitive disease in accordance with the methods provided herein is administered a Compound or a
  • a subject treated for an interferon-sensitive disease in accordance with the methods provided herein is a refractory patient.
  • a refractory patient is a patient refractory to a standard therapy.
  • a patient with an interferon-sensitive disease is refractory to a therapy when the interferon-sensitive disease has not significantly been eradicated and/or the one or more symptoms have not been significantly alleviated.
  • the determination of whether a patient is refractory can be made either in vivo or in vitro by any method known in the art for assaying the effectiveness of a treatment of an interferon- sensitive disease, using art-accepted meanings of "refractory" in such a context.
  • a subject treated for an interferon-sensitive disease in accordance with the methods provided herein is an animal (e.g., a human or non-human animal) that has proven refractory to therapies other than treatment with a Compound, but is no longer on these therapies.
  • a subject treated for an interferon- sensitive disease in accordance with the methods provided herein is an animal (e.g., a human or non-human animal) already receiving one or more conventional therapies used to treat the interferon-sensitive disease.
  • a subject treated for an interferon- sensitive disease in accordance with the methods provided herein is an animal (e.g., a human or non-human animal) already receiving one or more conventional anti-cancer therapies, such as surgery, drug therapy such as chemotherapy, anti-androgen therapy or radiation.
  • conventional anti-cancer therapies such as surgery, drug therapy such as chemotherapy, anti-androgen therapy or radiation.
  • these patients are refractory patients, patients who are too young for conventional therapies, and patients with recurring tumors despite treatment with existing therapies.
  • a subject treated for an interferon-sensitive disease in accordance with the methods described herein or administered a Compound as an adjuvant in accordance with the methods provided herein is an animal (e.g., a human or non-human animal) susceptible to adverse reactions to conventional therapies.
  • a subject treated for an interferon-sensitive disease or administered a Compound as an adjuvant in accordance with the methods provided herein is an animal (e.g., a human or non-human animal) that has not received a therapy, e.g., drug therapy, surgery, or radiation therapy, prior to the administration of a Compound or a pharmaceutical composition thereof.
  • a subject treated for an interferon-sensitive disease in accordance with the methods provided herein is an animal (e.g., a human or non-human animal) that has received a therapy prior to administration of a Compound.
  • a subject treated for an interferon-sensitive disease in accordance with the methods provided herein is an animal (e.g., a human or non-human animal) that has experienced adverse side effects to the prior therapy or the prior therapy was discontinued due to unacceptable levels of toxicity to the human.
  • a subject treated for an interferon-sensitive disease in accordance with the methods described herein has cancer.
  • the subject with cancer has a cancer that has metastasized to other areas of the body, such as the bones, brain, lymph nodes, lung and liver.
  • the subject is in remission from the cancer.
  • the subject has a recurrence of the cancer.
  • the subject is experiencing recurrence of one or more tumors associated with cancer.
  • a subject treated for an interferon-sensitive disease in accordance with the methods described herein has an influenza virus disease or infection.
  • the influenza virus infection is an active infection.
  • influenza virus infection is chronic. 5.4.1.1 Viral Diseases
  • Viral infections and/or viral diseases that can be treated with the methods provided herein include those caused by the following non-limiting list of viruses:
  • papillomavirus (the causative agent of genital warts), human T cell leukemia virus, human T cell lymphoma virus, human T cell lymphotropic virus, influenza virus, Lassa fever virus, Marburg virus, measles virus, mumps virus, myxovirus, nairovirus, nanirnavirus, nariva virus, ndumo virus, Necrovirus, neethling virus, neopvirus, neurotropic virus, Newcastle disease virus, oncornavirus, orbivirus, orthomyxovirus, parainfluenza virus, paramyxovirus, parvovirus, picornavirus, rabies virus, respiratory syncytial virus, rhinovirus, rubella virus, rubeola virus, SARS virus, Sendai virus, simian immunodeficiency virus, simian
  • VSV vesicular stomatitis virus
  • the interferon-sensitive disease is caused by an influenza virus.
  • the influenza virus is an influenza A virus.
  • influenza A viruses include subtype H10N4, subtype H10N5, subtype H10N7, subtype H10N8, subtype H10N9, subtype HI 1N1, subtype HI 1N13, subtype HI 1N2, subtype HI 1N4, subtype HI 1N6, subtype HI 1N8, subtype HI 1N9, subtype H12N1, subtype H12N4, subtype H12N5, subtype H12N8, subtype H13N2, subtype H13N3, subtype H13N6, subtype H13N7, subtype H14N5, subtype H14N6, subtype H15N8, subtype H15N9, subtype H16N3, subtype H1N1, subtype H1N2, subtype H1N3, subtype H1N6, subtype H1N9, subtype H2N1, subtype H2N2, subtype
  • strains of influenza A virus include, but are not limited to: A/sw/Iowa/15/30 (HlNl); A/WSN/33 (HlNl); A/eq/Prague/1/56 (H7N7); A/PR/8/34;
  • H2N2 A/mallard/Potsdam/178-4/83
  • H16N3 A/herring gull/DE/712/88
  • H16N3 A/sw/Hong Kong/168/1993
  • HlNl A/mallard/Alberta/211/98
  • HlNl A/shorebird/Delaware/168/06
  • H16N3 A/sw/Netherlands/25/80 (HlNl); A/sw/Germany/2/81 (HlNl);
  • A/sw/Hannover/1/81 HlNl
  • A/sw/Potsdam/1/81 HlNl
  • A/sw/Potsdam/ 15/81 HlNl
  • A/sw/Potsdam/268/81 HlNl
  • A/sw/Fi concludedre/2899/82 HlNl
  • A/sw/Potsdam/35/82 H3N2
  • A/sw/Cote d'Armor/3633/84 H3N2
  • A/sw/Gent/1/84 H3N2
  • a sw/Bakum/1362/98 H3N2; A sw/Italy/ 1521/98 (H1N2); A sw/Italy/1553-2/98 (H3N2); A sw/Italy/1566/98 (HlNl); A sw/Italy/ 1589/98 (HlNl); A sw/Bakum/8602/99 (H3N2); A sw/Cotes d'Armor/604/99 (H1N2); A sw/Cote d'Armor/1482/99 (HlNl);
  • a sw/Gent/7625/99 H1N2; A/Hong Kong/1774/99 (H3N2); A sw/Hong Kong/5190/99 (H3N2); A sw/Hong Kong/5200/99 (H3N2); A sw/Hong Kong/5212/99 (H3N2); A sw/IUe et Villaine/1455/99 (HlNl); A sw/Italy/1654- 1/99 (H1N2); A sw/Italy/2034/99 (HlNl);
  • H3N2 Kong/7982/00
  • H1N2 A sw/Italy/1081/00
  • HlNl A sw/Belzig/2/01
  • a sw/Belzig/54/01 H3N2
  • a sw/Hong Kong/9296/01 H3N2
  • a sw/Hong Kong/9745/01 H3N2
  • a sw/Spain/33601/01 H3N2
  • a sw/Hong Kong/1144/02 H3N2
  • a sw/Hong Kong/1197/02 H3N2
  • A/sw/Spain/39139/02 H3N2
  • a sw/Spain/42386/02 H3N2
  • a sw/Bissendorf/IDT 1864/03 H3N2
  • a sw/Ehren IDT2570/03 H1N2
  • A/sw/Gescher/IDT2702/03 H1N2
  • A/sw/Haselvinne/2617/03hp HlNl
  • A/sw/Norden/IDT2308/03 H1N2; A/sw/Spain/50047/03 (HlNl); A/sw/Spain/51915/03 (HlNl); A/sw/Vechta/2623/03 (HlNl); A/sw/Visbek IDT2869/03 (H1N2);
  • A/sw/Krogel/IDT4192/05 HlNl
  • a sw/Laer/IDT3893/05 HlNl
  • A/sw/Laer/IDT4126/05 H3N2
  • A/sw/Merzen IDT4114/05 H3N2
  • A/sw/Muesleringen-S./IDT4263/05 H3N2
  • A/sw/Osterhofen/IDT4004/05 H3N2
  • H1N2 A/sw/Krogel/IDT4192/05
  • H3N2 A sw/Laer/IDT3893/05
  • A/sw/Laer/IDT4126/05 H3N2
  • A/sw/Merzen IDT4114/05 H3N2
  • H3N2 A sw/Herzlake/IDT5337/06 (H3N2); A/wild boar/Germany/R 169/2006 (H3N2), rA/Brevig Mission/1/1918 (HlNl), A/Hong Kong/1/1968 (H3N2), A/Udorn/307/1972 (H3N2), A/USSR/90/1977 (HlNl), A/swine/Texas/4199-2/1998 (H3N2), rA/Vietnam/ 1203/2004 (H5N1), and A/California/04/2009 (HlNl).
  • strains of influenza A virus include, but are not limited to: A/Toronto/3141/2009 (HlNl); A/Regensburg/D6/2009 (HlNl); A/Bayern/62/2009 (HlNl); A/Bayern/62/2009 (HlNl); A/Bradenburg/ 19/2009 (HlNl); A/Bradenburg/20/2009 (HlNl); A/Distrito Federal/2611/2009 (HlNl); A/Mato Grosso/2329/2009 (HlNl); A/Sao Paulo/1454/2009 (HlNl); A/Sao Paulo/2233/2009 (HlNl); A/Stockholm/37/2009 (HlNl); A/Stockholm/41/2009 (HlNl); A/Stockholm/45/2009 (HlNl); A/swine/Alberta/OTH-33- 1/2009 (HlNl); A/swine
  • A/Osaka/180/2009 H1N1; A/Puerto Montt/Bio87/2009 (HI Nl); A/Sao Paulo/2303/2009 (mm); A/Sapporo/1/2009 (H1N1); A/Stockholm/30/2009 (mm); A/Stockholm/31/2009 (mm); A/Stockholm/32/2009 (mm); A/Stockholm/33/2009 (mm);
  • A/Stockholm/40/2009 ( ⁇ 1 1;) A/Stockholm/42/2009 (mm); A/Stockholm/43/2009 (H1N1); A/Stockholm/44/2009 (H1N1); A/Utsunomiya/2/2009 (H1N1);
  • influenza virus is an influenza B virus.
  • influenza B viruses include strain Aichi/5/88, strain Akita/27/2001, strain Akita/5/2001, strain Alaska/16/2000, strain Alaska/1777/2005, strain Argentina/69/2001, strain Arizona/ 146/2005, strain Arizona/148/2005, strain Bangkok/163/90, strain
  • strain Finland/ 164/2003 strain Finland/ 172/91, strain Finland/ 173/2003, strain Finland/ 176/2003, strain Finland/184/91, strain Finland/188/2003, strain Finland/ 190/2003, strain
  • strain Shiga/T30/98 strain Sichuan/379/99, strain Singapore/222/79, strain Spain/WV27/2002, strain Swiss/10/90, strain Switzerland/5441/90, strain Taiwan/0409/00, strain Taiwan/0722/02, strain
  • Taiwan/97271/2001 strain Tehran/80/02, strain Tokyo/6/98, strain Trieste/28/02, strain Ulan Ude/4/02, strain United Kingdom/34304/99, strain USSR/100/83, strain Victoria/103/89, strain Vienna/1/99, strain Wuhan/356/2000, strain WV194/2002, strain Xuanwu/23/82, strain Yamagata/1311/2003, strain Yamagata/K500/2001, strain Yamagata/ 16/88, strain
  • influenza virus is an influenza C virus.
  • influenza C viruses include strain Aichi/1/81, strain Ann Arbor/1/50, strain Aomori/74, strain California/78, strain England/83, strain Greece/79, strain
  • strain pig/Beijing/115/81 strain Saitama/3/2000) , strain Shizuoka/79, strain Yamagata/2/98, strain Yamagata/6/2000, strain Yamagata/9/96, strain BERLIN/1/85, strain ENGLAND/892/8, strain GREAT LAKES/1167/54, strain JJ/50, strain PIG/BEIJING/ 10/81, strain
  • the interferon-sensitive disease is cancer.
  • cancers that can be treated in accordance with the methods provided herein include: leukemias, such as but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias, such as, myeloblastic, promyelocytic, myelomonocytic, monocytic, and erythroleukemia leukemias and myelodysplastic syndrome; chronic leukemias, such as but not limited to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, hairy cell leukemia; polycythemia vera; lymphomas such as but not limited to Hodgkin's disease, non-Hodgkin's disease; multiple myelomas such as but not limited to smoldering multiple myeloma, nonsecretory myeloma, osteosclerotic my
  • breast cancer including but not limited to ductal carcinoma, adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, Paget's disease, and inflammatory breast cancer; adrenal cancer such as but not limited to pheochromocytom and adrenocortical carcinoma; thyroid cancer such as but not limited to papillary or follicular thyroid cancer, medullary thyroid cancer and anaplastic thyroid cancer; pancreatic cancer such as but not limited to, insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor;
  • pituitary cancers such as but limited to Cushing's disease, prolactin-secreting tumor, acromegaly, and diabetes insipius; eye cancers such as but not limited to ocular melanoma such as iris melanoma, choroidal melanoma, and cilliary body melanoma, and
  • vaginal cancers such as squamous cell carcinoma, adenocarcinoma, and melanoma
  • vulvar cancer such as squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget's disease
  • cervical cancers such as but not limited to, squamous cell carcinoma, and adenocarcinoma
  • uterine cancers such as but not limited to endometrial carcinoma and uterine sarcoma
  • ovarian cancers such as but not limited to, ovarian epithelial carcinoma, borderline tumor, germ cell tumor, and stromal tumor;
  • esophageal cancers such as but not limited to, squamous cancer, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; stomach cancers such as but not limited to, adenocarcinoma, fungating (polypoid), ulcerating, superficial spreading, diffusely spreading, malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; colon cancers; rectal cancers; liver cancers such as but not limited to hepatocellular carcinoma and hepatoblastoma; gallbladder cancers such as adenocarcinoma; cholangiocarcinomas such as but not limited to papillary, nodular, and diffuse; lung cancers such as non-small cell lung cancer, squamous cell
  • cancers include myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma and papillary adenocarcinomas (for a review of such disorders, see Fishman et al., 1985, Medicine, 2d Ed., J.B. Lippincott Co., Philadelphia and Murphy et al., 1997 ', Informed Decisions: The Complete Book of Cancer Diagnosis,
  • carcinoma including that of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid and skin; including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T cell lymphoma, Burkitt's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyoscarcoma; other tumors, including melanoma, seminoma, tetratocarcinoma, neuroblastoma and gli
  • Cancers associated with aberrations in apoptosis are also included and are not be limited to, follicular lymphomas, carcinomas with p53 mutations, hormone dependent tumors of the breast, prostate and ovary, and precancerous lesions such as familial adenomatous polyposis, and myelodysplastic syndromes.
  • malignancy or dysproliferative changes such as metaplasias and dysplasias
  • hyperproliferative disorders of the skin, lung, liver, bone, brain, stomach, colon, breast, prostate, bladder, kidney, pancreas, ovary, and/or uterus are encompassed herein.
  • Non-limiting examples of leukemias and other blood-borne cancers include acute lymphoblastic leukemia "ALL”, acute lymphoblastic B-cell leukemia, acute lymphoblastic T- cell leukemia, acute myeloblasts leukemia "AML”, acute promyelocyte leukemia "APL”, acute monoblastic leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocyctic leukemia, acute undifferentiated leukemia, chronic myelocytic leukemia "CML”, chronic lymphocytic leukemia "CLL”, and hairy cell leukemia.
  • ALL acute lymphoblastic leukemia
  • ALL acute lymphoblastic B-cell leukemia
  • acute lymphoblastic T- cell leukemia acute myeloblasts leukemia
  • AML acute promyelocyte leukemia
  • APL acute monoblastic leukemia
  • Non-limiting examples of lymphomas include Hodgkin's disease, non-Hodgkin's Lymphoma, Multiple myeloma, Waldenstrom's macroglobulinemia, Heavy chain disease, and Polycythemia vera.
  • Non-limiting examples of solid tumors that can be treated in accordance with the methods provided herein include, but are not limited to fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma,
  • endotheliosarcoma lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer, oral cancer, nasal cancer, throat cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, small cell lung carcinoma, bladder carcinoma, lung
  • meduUoblastoma meduUoblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, skin cancer, melanoma, neuroblastoma, and retinoblastoma.
  • a Compound is administered to a subject with an interferon-sensitive disease that is not a viral infection and not cancer, e.g., the interferon- sensitive disease is multiple sclerosis.
  • a Compound is administered to a subject with a pre-malignant condition, e.g., actinic keratosis.
  • a Compound is administered to a subject with leukocyte adhesion deficiency type I; Peyronie's disease; ulcerative colitis; Crohn's disease; osteoporosis; or chronic hepatitis.
  • leukocyte adhesion deficiency type I Peyronie's disease
  • ulcerative colitis Crohn's disease
  • osteoporosis or chronic hepatitis.
  • a Compound When administered to a patient, a Compound is preferably administered as a component of a composition that optionally comprises a pharmaceutically acceptable carrier vehicle.
  • the composition can be administered orally, or by any other convenient route, for example, topically, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal, and intestinal mucosa) and may be administered together with another biologically active agent. Administration can be systemic or local.
  • Various delivery systems are known, e.g., encapsulation in liposomes,
  • microparticles can be used to administer a Compound and pharmaceutically acceptable salts thereof.
  • Methods of administration include but are not limited to parenteral, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectally, by inhalation, or topically, particularly to the ears, nose, eyes, or skin.
  • the mode of administration is left to the discretion of the practitioner. In most instances, administration will result in the release of a Compound into the bloodstream.
  • a Compound may be desirable to administer a Compound locally. This may be achieved, for example, and not by way of limitation, by local infusion, topical application, e.g., in conjunction with a wound dressing, by injection, by means of a catheter, by means of a suppository, or by means of an implant, said implant being of a porous, non- porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
  • Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant.
  • a Compound is formulated as a suppository, with traditional binders and vehicles such as triglycerides.
  • a Compound can be administered topically, ocularly, intranasally or by an inhaler or nebulizer.
  • a Compound is delivered in a vesicle, in particular a liposome (See Langer, 1990, Science 249: 1527 1533; Treat et al, in Liposomes in the Therapy of Infectious Disease and Bacterial infection, Lopez -Berestein and Fidler (eds.), Liss, New York, pp. 353 365 (1989); Lopez Berestein, ibid., pp. 317 327; See generally ibid.).
  • a liposome See Langer, 1990, Science 249: 1527 1533; Treat et al, in Liposomes in the Therapy of Infectious Disease and Bacterial infection, Lopez -Berestein and Fidler (eds.), Liss, New York, pp. 353 365 (1989); Lopez Berestein, ibid., pp. 317 327; See generally ibid.).
  • a Compound is delivered in a controlled release system (See, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115 138 (1984)). Examples of controlled-release systems are discussed in the review by Langer, 1990, Science 249: 1527 1533 may be used.
  • a pump may be used (See Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201; Buchwald et al, 1980, Surgery 88:507; Saudek et al, 1989, N. Engl. J. Med. 321 :574).
  • polymeric materials can be used (See Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Florida (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J. Macromol. Sci. Rev. Macromol. Chem. 23:61; See also Levy et al, 1985, Science 228: 190; During et al, 1989, Ann. Neurol. 25:351; Howard et al, 1989, J. Neurosurg. 71 : 105).
  • combination therapies for the treatment of an interferon- sensitive disease which involve the administration of a Compound in combination with one or more additional therapies to a subject in need thereof.
  • combination therapies for the treatment of an interferon-sensitive disease which involve the administration of an effective amount of a Compound in combination with an effective amount of another therapy to a subject in need thereof
  • Therapeutic or prophylactic agents that can be used in combination with a Compound for the treatment of an interferon-sensitive disease include, but are not limited to, small molecules, synthetic drugs, peptides (including cyclic peptides), polypeptides, proteins, nucleic acids (e.g., DNA and RNA nucleotides including, but not limited to, antisense nucleotide sequences, triple helices, RNAi, and nucleotide sequences encoding biologically active proteins, polypeptides or peptides), antibodies, synthetic or natural inorganic molecules, mimetic agents, and synthetic or natural organic molecules.
  • synthetic drugs peptides (including cyclic peptides), polypeptides, proteins, nucleic acids (e.g., DNA and RNA nucleotides including, but not limited to, antisense nucleotide sequences, triple helices, RNAi, and nucleotide sequences encoding biologically active proteins, polypeptides or peptides),
  • agents that can be administered in combination with a Compound include, but are not limited to, vaccines, immunomodulatory agents (e.g., interferon), chemotherapeutic agents, anti-inflammatory agents (e.g., adrenocorticoids, corticosteroids (e.g., beclomethasone, budesonide, flunisolide, fluticasone, triamcinolone, methylprednisolone, prednisolone, prednisone, hydrocortisone), glucocorticoids, steroids, and non-steroidal anti-inflammatory drugs (e.g., aspirin, ibuprofen, diclofenac, and COX-2 inhibitors), pain relievers, leukotreine antagonists (e.g., montelukast, methyl xanthines, zafirlukast, and zileuton), beta2-agonists (e.g.
  • immunomodulatory agents e.g., interferon
  • albuterol e.g., albuterol, biterol, fenoterol, isoetharie, metaproterenol, pirbuterol, salbutamol, terbutalin formoterol, salmeterol, and salbutamol terbutaline
  • anticholinergic agents e.g., ipratropium bromide and oxitropium bromide
  • sulphasalazine penicillamine, dapsone
  • antihistamines e.g., anti-malarial agents
  • anti-viral agents e.g., nucleoside analogs (e.g., zidovudine, acyclovir, gangcyclovir, vidarabine, idoxuridine, trifluridine, and ribavirin), foscarnet, amantadine, rimantadine, saquinavir, indinavir, ritonavir, and AZT), antibacterial; agents, and antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, erythomycin, penicillin,
  • nucleoside analogs e.g., zidovudine, acyclovir, gangcyclovir, vidarabine, idoxuridine, trifluridine, and ribavirin
  • foscarnet amantadine, rimantadine, saquinavir, indinavir, ritonavir, and AZT
  • antibiotics e.g.
  • a Compound is administered in combination with a vaccine.
  • Any therapy which is known to be useful, or which has been used or is currently being used for the prevention, management, and/or treatment of an interferon-sensitive disease or symptom or disease associated therewith can be used in combination with a Compound. See, e.g., Gilman et ah, Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 10th ed., McGraw-Hill, New York, 2001; The Merck Manual of Diagnosis and Therapy, Berkow, M.D. et ah (eds.), 17th Ed., Merck Sharp & Dohme Research
  • the one or more other therapies that are administered in combination with a Compound are administered as supportive measures, such as pain relievers, anti-fever medications, or other therapies that alleviate or assist in the treatment of the interferon-sensitive disease
  • the therapies are administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, at about 1 hour apart, at about 1 to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours apart.
  • two or more therapies are administered within the same patent visit.
  • the interval of time between the administration of a Compound and the administration of one or more additional therapies may be about 1-5 minutes, 1-30 minutes, 30 minutes to 60 minutes, 1 hour, 1-2 hours, 2-6 hours, 2-12 hours, 12-24 hours, 1-2 days, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 15 weeks, 20 weeks, 26 weeks, 52 weeks, 11-15 weeks, 15-20 weeks, 20-30 weeks, 30-40 weeks, 40-50 weeks, 1 month, 2 months, 3 months, 4 months 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1 year, 2 years, or any period of time in between.
  • a Compound and one or more additional therapies are administered less than 1 day, 1 week, 2 weeks, 3 weeks, 4 weeks, one month, 2 months, 3 months, 6 months, 1 year, 2 years, or 5 years apart
  • the combination therapies provided herein involve administering a Compound daily, and administering one or more additional therapies once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every month, once every 2 months (e.g., approximately 8 weeks), once every 3 months (e.g., approximately 12 weeks), or once every 4 months (e.g., approximately 16 weeks).
  • a Compound and one or more additional therapies are cyclically administered to a subject. Cycling therapy involves the administration of a Compound for a period of time, followed by the administration of one or more additional therapies for a period of time, and repeating this sequential administration.
  • cycling therapy may also include a period of rest where a Compound or the additional therapy is not administered for a period of time (e.g., 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 10 weeks, 20 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 2 years, or 3 years).
  • the number of cycles administered is from 1 to 12 cycles, from 2 to 10 cycles, or from 2 to 8 cycles.
  • the methods for treating an interferon-sensitive disease provided herein comprise administering a Compound as a single agent for a period of time prior to administering the Compound in combination with an additional therapy. In certain embodiments, the methods for treating an interferon-sensitive disease provided herein comprise administering an additional therapy alone for a period of time prior to administering a Compound in combination with the additional therapy.
  • the administration of a Compound and one or more additional therapies in accordance with the methods presented herein have an additive effect relative the administration of the Compound or said one or more additional therapies alone.
  • the administration of a Compound and one or more additional therapies in accordance with the methods presented herein have a synergistic effect relative to the administration of the Compound or said one or more additional therapies alone.
  • Compound and one or more additional therapies can be administered concurrently to a subject in separate pharmaceutical compositions.
  • a Compound and one or more additional therapies can be administered sequentially to a subject in separate pharmaceutical compositions.
  • a Compound and one or more additional therapies may also be administered to a subject by the same or different routes of administration.
  • the combination therapies provided herein involve administering to a subject to in need thereof a Compound in combination with conventional, or known, therapies for interferon-sensitive diseases.
  • Other therapies for an interferon-sensitive disease or a condition associated therewith are aimed at controlling or relieving one or more symptoms.
  • the combination therapies provided herein involve administering to a subject to in need thereof a pain reliever, or other therapies aimed at alleviating or controlling one or more symptoms associated with the interferon-sensitive disease or a condition associated therewith.
  • a combination therapy comprises the administration of one or more Compounds.
  • a combination therapy comprises administration of two or more Compounds.
  • Antiviral agents that can be used in combination with a Compound include, but are not limited to, non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors.
  • the antiviral agent is selected from the group consisting of amantadine, oseltamivir phosphate, rimantadine, and zanamivir.
  • the antiviral agent is a non-nucleoside reverse transcriptase inhibitor selected from the group consisting of delavirdine, efavirenz, and nevirapine.
  • the antiviral agent is a nucleoside reverse transcriptase inhibitor selected from the group consisting of abacavir, didanosine, emtricitabine, emtricitabine, lamivudine, stavudine, tenofovir DF, zalcitabine, and zidovudine.
  • the antiviral agent is a protease inhibitor selected from the group consisting of amprenavir, atazanavir, fosamprenav, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir.
  • the antiviral agent is a fusion inhibitor such as enfuvirtide.
  • Other examples of anti-viral agents include but are not limited to acemannan; acyclovir; acyclovir sodium; adefovir; alovudine; alvircept sudotox; amantadine
  • cidofovir cipamfylline
  • cytarabine hydrochloride delavirdine mesylate
  • desciclovir delavirdine mesylate
  • ganciclovir ganciclovir sodium; idoxuridine; kethoxal; lamivudine; lobucavir; memotine hydrochloride; methisazone; nevirapine; oseltamivir phosphate (TAMIFLUTM); penciclovir; pirodavir; ribavirin; rimantadine hydrochloride (FLUMADINETM); saquinavir mesylate; somantadine hydrochloride; sorivudine; statolon; stavudine; tilorone hydrochloride;
  • the anti-viral agent is an immunomodulatory agent that is specific for a viral antigen.
  • the viral antigen is an influenza virus polypeptide other than a hemagglutinin polypeptide. In other embodiments, the viral antigen is an influenza virus hemagglutinin polypeptide.
  • Antibacterial agents including antibiotics, that can be used in combination with a Compound include, but are not limited to, aminoglycoside antibiotics, glycopeptides, amphenicol antibiotics, ansamycin antibiotics, cephalosporins, cephamycins oxazolidinones, penicillins, quinolones, streptogamins, tetracyclins, and analogs thereof.
  • aminoglycoside antibiotics glycopeptides
  • amphenicol antibiotics ansamycin antibiotics
  • cephalosporins cephamycins oxazolidinones
  • penicillins quinolones
  • streptogamins tetracyclins
  • antibiotics are administered in combination with a Compound to prevent and/or treat a bacterial infection.
  • Compounds are used in combination with other protein synthesis inhibitors, including but not limited to, streptomycin, neomycin, erythromycin, carbomycin, and spiramycin.
  • the antibacterial agent is selected from the group consisting of ampicillin, amoxicillin, ciprofloxacin, gentamycin, kanamycin, neomycin, penicillin G, streptomycin, sulfanilamide, and vancomycin.
  • the antibacterial agent is selected from the group consisting of azithromycin, cefonicid, cefotetan, cephalothin, cephamycin, chlortetracycline, clarithromycin, clindamycin, cycloserine, dalfopristin, doxycycline, erythromycin, linezolid, mupirocin, oxytetracycline, quinupristin, rifampin, spectinomycin, and trimethoprim.
  • antibacterial agents for use in combination with a Compound include the following: aminoglycoside antibiotics (e.g., apramycin, arbekacin, bambermycins, butirosin, dibekacin, neomycin, neomycin, undecylenate, netilmicin, paromomycin, ribostamycin, sisomicin, and spectinomycin), amphenicol antibiotics (e.g., azidamfenicol, chloramphenicol, florfenicol, and thiamphenicol), ansamycin antibiotics (e.g., rifamide and rifampin), carbacephems (e.g., loracarbef), carbapenems (e.g., biapenem and imipenem), cephalosporins (e.g., cefaclor, cefadroxil, cefamandole, cefatrizine
  • aminoglycoside antibiotics e
  • quinolones and analogs thereof e.g., cinoxacin, ciprofloxacin, clinafloxacin, flumequine, grepagloxacin, levofloxacin, and moxifloxacin
  • streptogramins e.g., quinupristin and dalfopristin
  • sulfonamides e.g., acetyl sulfamethoxypyrazine, benzylsulfamide, noprylsulfamide, phthalylsulfacetamide,
  • sulfachrysoidine and sulfacytine
  • sulfones e.g., diathymosulfone, glucosulfone sodium, and solasulfone
  • tetracyclines e.g., apicycline, chlortetracycline, clomocycline, and demeclocycline
  • Additional examples include cycloserine, mupirocin, tuberin amphomycin, bacitracin, capreomycin, colistin, enduracidin, enviomycin, and 2,4 diaminopyrimidines (e.g., brodimoprim).
  • anti-cancer agents that may be used in combination with a Compound include: hormonal agents (e.g., aromatase inhibitor, selective estrogen receptor modulator (SERM), and estrogen receptor antagonist), chemotherapeutic agents (e.g., microtubule dissembly blocker, antimetabolite, topisomerase inhibitor, and DNA crosslinker or damaging agent), anti-angiogenic agents (e.g., VEGF antagonist, receptor antagonist, integrin antagonist, vascular targeting agent (VTA)/vascular disrupting agent (VDA)), radiation therapy, and conventional surgery.
  • hormonal agents e.g., aromatase inhibitor, selective estrogen receptor modulator (SERM), and estrogen receptor antagonist
  • chemotherapeutic agents e.g., microtubule dissembly blocker, antimetabolite, topisomerase inhibitor, and DNA crosslinker or damaging agent
  • anti-angiogenic agents e.g., VEGF antagonist, receptor antagonist, integrin antagonist, vascular targeting agent (VTA)/vascular disrupting agent
  • Non-limiting examples of hormonal agents that may be used in combination with a Compound include aromatase inhibitors, SERMs, and estrogen receptor antagonists.
  • Hormonal agents that are aromatase inhibitors may be steroidal or nonsteroidal.
  • Non-limiting examples of nonsteroidal hormonal agents include letrozole, anastrozole, aminoglutethimide, fadrozole, and vorozole.
  • Non-limiting examples of steroidal hormonal agents include aromasin (exemestane), formestane, and testolactone.
  • Non-limiting examples of hormonal agents that are SERMs include tamoxifen (branded/marketed as Nolvadex ® ), afimoxifene, arzoxifene, avalycoxifene, clomifene, femarelle, lasofoxifene, ormeloxifene, raloxifene, and toremifene.
  • Non-limiting examples of hormonal agents that are estrogen receptor antagonists include fulvestrant.
  • Other hormonal agents include but are not limited to abiraterone and lonaprisan.
  • Non-limiting examples of chemotherapeutic agents that may be used in combination with a Compound include microtubule disasssembly blocker, antimetabolite, topisomerase inhibitor, and DNA crosslinker or damaging agent.
  • Chemotherapeutic agents that are microtubule disassemby blockers include, but are not limited to, taxenes (e.g., paclitaxel (branded/marketed as TAXOL ® ), docetaxel, abraxane, larotaxel, ortataxel, and tesetaxel); epothilones (e.g., ixabepilone); and vinca alkaloids (e.g., vinorelbine, vinblastine, vindesine, and vincristine (branded/marketed as ONCOVIN ® )).
  • taxenes e.g., paclitaxel (branded/marketed as TAXOL ® ), docetaxel, abraxane, larotaxel, or
  • Chemotherapeutic agents that are antimetabolites include, but are not limited to, folate anitmetabolites (e.g., methotrexate, aminopterin, pemetrexed, raltitrexed); purine antimetabolites (e.g., cladribine, clofarabine, fludarabine, mercaptopurine, pentostatin, thioguanine); pyrimidine antimetabolites (e.g., 5-fluorouracil, capcitabine, gemcitabine (GEMZAR ® ), cytarabine, decitabine, floxuridine, tegafur); and deoxyribonucleotide antimetabolites (e.g., hydroxyurea).
  • folate anitmetabolites e.g., methotrexate, aminopterin, pemetrexed, raltitrexed
  • purine antimetabolites e.g., cladribine, clofarabine, fludarabine, mer
  • Chemotherapeutic agents that are topoisomerase inhibitors include, but are not limited to, class I (camptotheca) topoisomerase inhibitors (e.g., topotecan (branded/marketed as HYCAMTIN ® ) irinotecan, rubitecan, and belotecan); class II (podophyllum)
  • topoisomerase inhibitors e.g., etoposide or VP- 16, and teniposide
  • anthracyclines e.g., doxorubicin, epirubicin, Doxil, aclarubicin, amrubicin, daunorubicin, idarubicin, pirarubicin, valrubicin, and zorubicin
  • anthracenediones e.g., mitoxantrone, and pixantrone.
  • Chemotherapeutic agents that are DNA crosslinkers include, but are not limited to, alkylating agents (e.g., cyclophosphamide, mechlorethamine, ifosfamide (branded/marketed as IFEX ® ), trofosfamide, chlorambucil, melphalan, prednimustine, bendamustine, uramustine, estramustine, carmustine (branded/marketed as BiCNU ® ), lomustine, semustine, fotemustine, nimustine, ranimustine, streptozocin, busulfan, mannosulfan, treosulfan, carboquone, ⁇ , ⁇ ' ⁇ '-triethylenethiophosphoramide, triaziquone, triethylenemelamine); alkylating-like agents (e.g., carboplatin (branded/marketed as
  • PARAPLATIN ® cisplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, satraplatin, picoplatin
  • nonclassical DNA crosslinkers e.g., procarbazine, dacarbazine, temozolomide (branded/marketed as TEMODAR ® ), altretamine, mitobronitol
  • intercalating agents e.g., actinomycin, bleomycin, mitomycin, and plicamycin.
  • Any vaccine can be used in combination with a Compound in the compositions and methods described herein.
  • a non-limiting list of vaccines includes Anthrax vaccine, BCG vaccine, Diphtheria vaccine, tetanus vaccine, pertussis vaccine, haemophilus B vaccine, hepatitis A vaccine, hepatitis B vaccine, human papillomavirus vaccine, influenza vaccine, Japanese encephalitis virus vaccine, measles vaccine, mumps vaccine, plague vaccine, pneumococcal vaccine, poliovirus vaccine, rabies vaccine, respiratory syncytial virus (RSV) vaccine, rotavirus vaccine, rubella vaccine, smallpox vaccine, typhoid vaccine, varicella virus vaccine, yellow fever vaccine, and zoster vaccine.
  • Anthrax vaccine BCG vaccine
  • Diphtheria vaccine tetanus vaccine
  • pertussis vaccine haemophilus B vaccine
  • hepatitis A vaccine hepatitis B vaccine
  • the amount of a Compound, or the amount of a composition comprising a Compound, that will be effective in the treatment of an interferon-sensitive disease can be determined by standard clinical techniques. In vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed will also depend, e.g. , on the route of administration, the type of interferon-sensitive disease, and the seriousness of the interferon-sensitive disease, and should be decided according to the judgment of the practitioner and each patient's or subject's circumstances.
  • the dosage of a Compound is determined by extrapolating from the "no observed adverse effective level" (NOAEL), as determined in animal studies. This extrapolated dosage is useful in determining the maximum recommended starting dose for human clinical trials.
  • NOAELs can be extrapolated to determine human equivalent dosages (HED).
  • HED is extrapolated from a non-human animal dosage based on the doses that are normalized to body surface area (i.e. , mg/m 2 ).
  • the NOAELs are determined in mice, hamsters, rats, ferrets, guinea pigs, rabbits, dogs, primates, primates (monkeys, marmosets, squirrel monkeys, baboons), micropigs or minipigs.
  • NOAELs are determined in mice, hamsters, rats, ferrets, guinea pigs, rabbits, dogs, primates, primates (monkeys, marmosets, squirrel monkeys, baboons), micropigs or minipigs.
  • a Compound or composition thereof is administered at a dose that is lower than the human equivalent dosage (HED) of the NOAEL over a period of 1 week, 2 weeks, 3 weeks, 1 month, 2 months, three months, four months, six months, nine months, 1 year, 2 years, 3 years, 4 years or more.
  • HED human equivalent dosage
  • a dosage regime for a human subject can be extrapolated from animal model studies using the dose at which 10% of the animals die (LDio).
  • LDio dose at which 10% of the animals die
  • a standard measure of toxicity of a drug in preclinical testing is the percentage of animals that die because of treatment. It is well within the skill of the art to correlate the LDio in an animal study with the maximal-tolerated dose (MTD) in humans, adjusted for body surface basis to extrapolate a starting human dose.
  • MTD maximal-tolerated dose
  • the interrelationship of dosages for one animal model can be converted for use in another animal, including humans, using conversion factors (based on milligrams per meter squared of body surface) as described, e.g., in Freireich et ah , Cancer Chemother. Rep., 1966, 50:219-244.
  • Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardley, N. Y., 1970, 537.
  • the adjustment for body surface area includes host factors such as, for example, surface area, weight, metabolism, tissue distribution, absorption rate, and excretion rate.
  • the route of administration, excipient usage, and the specific influenza virus or symptom thereof (and/or other disease) to target are also factors to consider.
  • the standard conservative starting dose is about 1/10 the murine LDio, although it may be even lower if other species (i.e., dogs) were more sensitive to the Compound.
  • the standard conservative starting dose is about 1/100, 1/95, 1/90, 1/85, 1/80, 1/75, 1/70, 1/65, 1/60, 1/55, 1/50, 1/45, 1/40, 1/35, 1/30, 1/25, 1/20, 1/15, 2/10, 3/10, 4/10, or 5/10 of the murine LDio.
  • a starting dose amount of a Compound in a human is lower than the dose extrapolated from animal model studies. In another embodiment, a starting dose amount of a Compound in a human is higher than the dose extrapolated from animal model studies. It is well within the skill of the art to start doses of the active composition at relatively low levels, and increase or decrease the dosage as necessary to achieve the desired effect with minimal toxicity.
  • the Compounds can be administered one to four times a day in a dose of about 0.005 mg/kg of a patient's body weight to about 10 mg/kg of a patient's body weight in a patient, but the above dosage may be properly varied depending on the age, body weight and medical condition of the patient and the type of administration.
  • the dose is about 0.01 mg/kg of a patient's body weight to about 5 mg/kg of a patient's body weight, about 0.05 mg/kg of a patient's body weight to about 1 mg/kg of a patient's body weight, about 0.1 mg/kg of a patient's body weight to about 0.75 mg/kg of a patient's body weight or about 0.25 mg/kg of a patient's body weight to about 0.5 mg/kg of a patient's body weight.
  • one dose is given per day.
  • the amount of the Compound administered will depend on such factors as the solubility of the active component, the formulation used and the route of administration.
  • kits for the treatment of an interferon-sensitive disease comprising the administration of about 0.375 mg/day to about 750 mg/day, about 0.75 mg/day to about 375 mg/day, about 3.75 mg/day to about
  • kits for the treatment of an interferon-sensitive disease comprising the administration of about 1 mg/day to about 1200 mg/day, about 10 mg/day to about 1200 mg/day, about 100 mg/day to about 1200 mg/day, about 400 mg/day to about 1200 mg/day, about 600 mg/day to about 1200 mg/day, about 400 mg/day to about 800 mg/day or about 600 mg/day to about 800 mg/day of a Compound to a patient in need thereof.
  • the methods disclosed herein comprise the administration of 400 mg/day, 600 mg/day or 800 mg/day of a Compound to a patient in need thereof.
  • unit dosage formulations that comprise between about 1 mg and about 2000 mg, about 1 mg and 200 mg, about 35 mg and about 1400 mg, about 125 mg and about 1000 mg, about 250 mg and about 1000 mg, or about 500 mg and about 1000 mg of a Compound.
  • unit dosage formulation comprising about 100 mg or 400 mg of a Compound.
  • unit dosage formulations that comprise 1 mg, 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg or 1400 mg of a Compound.
  • suitable dosage ranges for oral administration are about 0.001 milligram to about 500 milligrams of a Compound, per kilogram body weight per day.
  • the oral dose is about 0.01 milligram to about 100 milligrams per kilogram body weight per day, about 0.1 milligram to about 75 milligrams per kilogram body weight per day or about 0.5 milligram to 5 milligrams per kilogram body weight per day.
  • the dosage amounts described herein refer to total amounts administered; that is, if more than one Compound is administered, then, in some embodiments, the dosages correspond to the total amount administered.
  • oral compositions contain about 10% to about 95% of a Compound by weight.
  • Suitable dosage ranges for intravenous (i.v.) administration are about 0.01 milligram to about 100 milligrams per kilogram body weight per day, about 0.1 milligram to about 35 milligrams per kilogram body weight per day, and about 1 milligram to about 10 milligrams per kilogram body weight per day.
  • suitable dosage ranges for intranasal administration are about 0.01 pg/kg body weight per day to about 1 mg/kg body weight per day.
  • Suppositories generally contain about 0.01 milligram to about 50 milligrams of a Compound per kilogram body weight per day and comprise active ingredient in the range of about 0.5% to about 10%> by weight.
  • a subject is administered one or more doses of a prophylactically or therapeutically effective amount of a Compound or a composition described herein, wherein the effective amount is not the same for each dose.
  • the subject is administered a Compound or a composition described herein in an amount effective to inhibit viral genome replication by at least 20% to 25%, preferably at least 25% to 30%, at least 30% to 35%, at least 35% to 40%, at least 40% to 45%, at least 45% to 50%, at least 50% to 55%, at least 55% to 60%, at least 60% to 65%, at least 65% to 70%, at least 70% to 75%, at least 75% to 80%, or up to at least 85% relative to a negative control as determined using an assay described herein or others known to one of skill in the art.
  • a subject is administered a Compound or a composition in an amount effective to inhibit or reduce viral genome replication by at least 20% to 25%, preferably at least 25% to 30%, at least 30% to 35%, at least 35% to 40%, at least 40% to 45%, at least 45% to 50%, at least 50% to 55%, at least 55% to 60%, at least 60% to 65%, at least 65% to 70%, at least 70% to 75%, at least 75% to 80%, or up to at least 85% relative to a negative control as determined using an assay described herein or others known to one of skill in the art.
  • a subject is administered a Compound or a composition in an amount effective to inhibit or reduce viral genome replication by at least 1.5 fold, 2 fold, 2.5 fold, 3 fold, 4 fold, 5 fold, 8 fold, 10 fold, 15 fold, 20 fold, or 2 to 5 fold, 2 to 10 fold, 5 to 10 fold, or 5 to 20 fold relative to a negative control as determined using an assay described herein or other known to one of skill in the art.
  • the subject is administered a Compound or a composition described herein in an amount effective to inhibit or reduce viral protein synthesis by at least 20% to 25%, preferably at least 25% to 30%, at least 30% to 35%, at least 35% to 40%, at least 40% to 45%, at least 45% to 50%, at least 50% to 55%, at least 55% to 60%, at least 60% to 65%, at least 65% to 70%, at least 70% to 75%, at least 75% to 80%, or up to at least 85% relative to a negative control as determined using an assay described herein or others known to one of skill in the art.
  • a subject is administered a Compound or a composition in an amount effective to inhibit or reduce viral protein synthesis by at least 20% to 25%, preferably at least 25% to 30%, at least 30% to 35%, at least 35% to 40%, at least 40% to 45%, at least 45% to 50%, at least 50% to 55%, at least 55% to 60%, at least 60% to 65%, at least 65% to 70%, at least 70% to 75%, at least 75% to 80%, or up to at least 85% relative to a negative control as determined using an assay described herein or others known to one of skill in the art.
  • a subject is administered a Compound or a composition in an amount effective to inhibit or reduce viral protein synthesis by at least 1.5 fold, 2 fold, 2.5 fold, 3 fold, 4 fold, 5 fold, 8 fold, 10 fold, 15 fold, 20 fold, or 2 to 5 fold, 2 to 10 fold, 5 to 10 fold, or 5 to 20 fold relative to a negative control as determined using an assay described herein or others known to one of skill in the art.
  • the subject is administered a Compound or a composition described herein in an amount effective to inhibit or reduce the spread of virus from a cell, tissue, or organ to another cell, tissue or organ by at least 20% to 25%, preferably at least 25% to 30%, at least 30% to 35%, at least 35% to 40%, at least 40% to 45%, at least 45% to 50%, at least 50% to 55%, at least 55% to 60%, at least 60% to 65%, at least 65% to 70%, at least 70% to 75%, at least 75% to 80%, or up to at least 85% relative to a negative control as determined using an assay described herein or others known to one of skill in the art.
  • a subject is administered a Compound or a composition in an amount effective to inhibit or reduce the spread of virus from a cell, tissue or organ to another cell, tissue or organ by at least 1.5 fold, 2 fold, 2.5 fold, 3 fold, 4 fold, 5 fold, 8 fold, 10 fold, 15 fold, 20 fold, or 2 to 5 fold, 2 to 10 fold, 5 to 10 fold, or 5 to 20 fold relative to a negative control as determined using an assay described herein or others known to one of skill in the art.
  • the subject is administered a Compound or a composition described herein in an amount effective to inhibit or reduce viral titer by at least 20% to 25%, preferably at least 25% to 30%, at least 30% to 35%, at least 35% to 40%, at least 40% to 45%, at least 45% to 50%, at least 50% to 55%, at least 55% to 60%, at least 60% to 65%, at least 65% to 70%, at least 70% to 75%, at least 75% to 80%, or up to at least 85% relative to a negative control as determined using an assay described herein or others known to one of skill in the art.
  • a subject is administered a Compound or a composition in an amount effective to inhibit or reduce viral titer by at least 1.5 fold, 2 fold, 2.5 fold, 3 fold, 4 fold, 5 fold, 8 fold, 10 fold, 15 fold, 20 fold, or 2 to 5 fold, 2 to 10 fold, 5 to 10 fold, or 5 to 20 fold relative to a negative control as determined using an assay described herein or others known to one of skill in the art.
  • a subject is administered a Compound or a composition in an amount effective to inhibit or reduce viral titer by 1 log, 1.5 logs, 2 logs, 2.5 logs, 3 logs, 3.5 logs, 4 logs, 5 logs or more relative to a negative control as determined using an assay described herein or others known to one of skill in the art.
  • the subject is administered a Compound or a composition described herein in an amount effective to inhibit or reduce viral replication by at least 20% to 25%, preferably at least 25% to 30%, at least 30% to 35%, at least 35% to 40%, at least 40% to 45%, at least 45% to 50%, at least 50% to 55%, at least 55% to 60%, at least 60% to 65%, at least 65% to 70%, at least 70% to 75%, at least 75% to 80%, or up to at least 85% relative to a negative control as determined using an assay described herein or others known to one of skill in the art.
  • a subject is administered a Compound or a composition in an amount effective to inhibit or reduce viral replication by at least 1.5 fold, 2 fold, 2.5 fold, 3 fold, 4 fold, 5 fold, 8 fold, 10 fold, 15 fold, 20 fold, or 2 to 5 fold, 2 to 10 fold, 5 to 10 fold, or 5 to 20 fold relative to a negative control as determined using an assay described herein or others known to one of skill in the art.
  • a subject is administered a Compound or a composition described herein in an amount effective to inhibit or reduce viral replication by 1 log, 1.5 logs, 2 logs, 2.5 logs, 3 logs, 3.5 logs, 4 logs, 5 logs or more relative to a negative control as determined using an assay described herein or others known to one of skill in the art.
  • the subject is administered a Compound or a composition described herein in an amount effective to inhibit or reduce the ability of the virus to spread to other individuals by at least 20% to 25%, preferably at least 25% to 30%, at least 30% to 35%, at least 35% to 40%, at least 40% to 45%, at least 45% to 50%, at least 50% to 55%, at least 55% to 60%, at least 60% to 65%, at least 65% to 70%, at least 70% to 75%, at least 75% to 80%, or up to at least 85% relative to a negative control as determined using an assay described herein or others known to one of skill in the art.
  • a subject is administered a Compound or a composition in an amount effective to inhibit or reduce the ability of the virus to spread to other cells, tissues or organs in the subject by at least 20% to 25%, preferably at least 25% to 30%, at least 30% to 35%, at least 35% to 40%, at least 40% to 45%, at least 45% to 50%, at least 50% to 55%, at least 55% to 60%, at least 60% to 65%, at least 65% to 70%, at least 70% to 75%, at least 75% to 80%, or up to at least 85% relative to a negative control as determined using an assay described herein or others known to one of skill in the art.
  • the subject is administered a Compound or a composition described herein in an amount effective to inhibit cancer cell replication by at least 20% to 25%, preferably at least 25% to 30%, at least 30% to 35%, at least 35% to 40%, at least 40% to 45%, at least 45% to 50%, at least 50% to 55%, at least 55% to 60%, at least 60% to 65%, at least 65% to 70%, at least 70% to 75%, at least 75% to 80%, or up to at least 85% relative to a negative control as determined using an assay described herein or others known to one of skill in the art.
  • a subject is administered a Compound or a composition in an amount effective to inhibit cancer cell replication by at least 1.5 fold, 2 fold, 2.5 fold, 3 fold, 4 fold, 5 fold, 8 fold, 10 fold, 15 fold, 20 fold, or 2 to 5 fold, 2 to 10 fold, 5 to 10 fold, or 5 to 20 fold relative to a negative control as determined using an assay described herein or other known to one of skill in the art.
  • the interferon-sensitive disease in a subject is cancer
  • the subject is administered a Compound or a composition described herein in an amount effective to reduce or stabilize the size of a tumor.
  • the interferon-sensitive disease in a subject is cancer
  • the subject is administered a Compound or a composition described herein in an amount effective to prevent the spread of the cancer (i.e., metastasis) in the subject.
  • a dose of a Compound or a composition described herein is administered to a subject every day, every other day, every couple of days, every third day, once a week, twice a week, three times a week, or once every two weeks.
  • two, three or four doses of a Compound or a composition described herein is administered to a subject every day, every couple of days, every third day, once a week or once every two weeks.
  • a dose(s) of a Compound or a composition is administered for 2 days, 3 days, 5 days, 7 days, 14 days, or 21 days.
  • a dose of a Compound or a composition described herein is administered for 1 month, 1.5 months, 2 months, 2.5 months, 3 months, 4 months, 5 months, 6 months or more.
  • the dosages of prophylactic or therapeutic agents which have been or are currently used for the prevention, treatment and/or management of an interferon-sensitive disease can be determined using references available to a clinician such as, e.g., the
  • dosages lower than those which have been or are currently being used to prevent, treat and/or manage the interferon-sensitive disease are utilized in combination with one or more Compounds or compositions described herein.
  • a Compound is used to increase interferon production in cultured cells.
  • a Compound may be added to cultured cells to induce interferon production by the cultured cells.
  • a compound is added to cultured cells to induce production of recombinant interferon by the cells.
  • the interferon produced by the cultured cells is collected and used for a secondary application, such as for a treatment of a condition recited herein.
  • the interferon produced by the cells is isolated/purified.
  • a Compound is used to increase interferon production in cells cultured in a bioreactor.
  • the interferon produced by the cells is recombinant interferon.
  • the interferon is collected and used for a secondary application, such as for a treatment of a condition recited herein.
  • the interferon produced by the cells is isolated/purified.
  • kits comprising one or more containers filled with a Compound or a pharmaceutical composition thereof. Also provided herein are pharmaceutical kits comprising one or more containers filled with a Compound or a pharmaceutical composition thereof and one or more containers filled with one or more of the ingredients of the pharmaceutical compositions described herein. Additionally, instructions for the use (e.g. , relating to the dosage amount, dosing frequency or route(s) of
  • kits can also be included in the pharmaceutical kit.
  • Optionally associated with such kits can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
  • kits for use in a research or laboratory setting comprising one or more containers filled with a Compound.
  • Such kits can further comprise instructions for carrying out a laboratory experiment or procedure, such as that wherein the Compound(s) is used as a standard or control.
  • Such kits can further comprise one or more containers filled with additional reagents useful or needed for carrying out a laboratory experiment or procedure.
  • Such kits can further comprise cells that express a reporter gene (e.g., a luciferase reporter gene) operably linked to an interferon promoter.
  • Such kits can further comprise a vector that expresses a reporter gene (e.g., a luciferase reporter gene) operably linked to an interferon promoter gene.
  • a method of inhibiting or reducing replication of an influenza virus in a subject comprising administering to a subject in need thereof an effective amount of a Compound, wherein the Compound has the structure:
  • the subject is a human.
  • a method of treating an influenza virus infection or a symptom associated therewith in a subject comprising administering to a subject in need thereof an effective amount of a Compound, wherein the Compound has the structu
  • the subject is a human.
  • a method of preventing a symptom associated with an influenza virus infection in a subject comprising administering to a subject in need thereof an effective amount of a Compound, wherein the Compound has the structure:
  • the subject is a human.
  • a method of treating an influenza virus disease in a subject comprising administering to a subject in need thereof an effective amount of a Compound, wherein the Compound has the structure:
  • the subject is a human.
  • a method of preventing a symptom associated with an influenza virus disease in a subject comprising administering to a subject in need thereof an effective amount of a Compound, wherein the Compound has the structure:
  • the subject is a human.
  • a method for treating an interferon-sensitive disease comprising administering to a subject in need thereof an effective amount of a Compound, wherein the Compound has the structure:
  • the subject is a human.
  • a method for treating an interferon- sensitive disease comprising administering to a subject in need thereof an effective amount of a Compound, wherein the Compound has the formula:
  • R 1 of formula I is substituted or unsubstituted heterocyclyl; and R 2 of formula 1 is H or OH;
  • X of formula II is CH or N; and R 1 , R 2 , R 3 and R 4 of formula II are at each occurrence independently hydrogen or substituted or unsubstituted Ci -4 alkyl;
  • R 1 and R 2 of formula III are at each occurrence independently substituted or unsubstituted Ci -4 alkyl, or R 1 and R 2 of formula III taken together with the nitrogen atom to which they are attached form substituted or unsubstituted heterocyclyl; and
  • R 1 of formula IV is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and R 2 of formula IV is substituted or unsubstituted Ci -4 alkyl, substituted or unsubstituted C2- 4 alkenyl or substituted or unsubstituted heteroaryl,
  • the compound of formula I is not doxorubicin or daunorubicin and the compound of formula II is not aminacrine.
  • the compound of formula II is not aminacrine.
  • R 1 of formula I is substituted tetrahydro-2H-pyran
  • R 1 , R 2 , R 3 and R 4 of formula II are methyl
  • R 1 and R 2 of formula III are each ethyl, or R 1 and R 2 of formula III taken together with the nitrogen atom to which they are attached form piperidine; and [00327] (iv) R 1 of formula IV is substituted or unsubstituted furan, thiophene or phenyl; and R 2 of formula IV is substituted or unsubstituted alkoxyalkyl, arylalkyl, allyl, propyl or alkoxyalkyl.
  • the subject is a human.
  • a method for treating an interferon-sensitive disease comprising administering to a subject in need thereof an effective amount of a Compound, wherein the Compound has the structure:
  • the subject is human.
  • a method for treating an influenza virus disease comprising administering to a subject in need thereof an effective amount of a Compound, wherein the Compound has the structure:
  • influenza virus is an influenza A virus.
  • influenza A virus is subtype H1N1, H3N2, or H5N1.
  • the subject is human.
  • the interferon-sensitive disease is caused by a viral infection, such as, e.g. , influenza virus, adenovirus, arbovirus, paramyxovirus, baculovirus, coronavirus, papillomavirus, parvovirus, chickenpox virus, reovirus, Ebola virus, Ebola-like virus, echo virus, encephalitis virus, filovirus, hantavirus, hepatitis virus, German measles virus, cytomegalovirus, hemorrhagic fever virus, herpes simplex virus, hepatitis B virus, hepatitis C virus, human immunodeficiency virus, human papillomavirus, human T cell leukemia virus, human T cell lymphoma virus, human T cell lymphotropic virus, Lassa fever virus, Marburg virus, measles virus, mumps virus, myxovirus, nairovirus, nanima
  • a viral infection such as, e.g
  • the interferon-sensitive disease is caused by a bacterial infection.
  • the interferon-sensitive disease is multiple sclerosis.
  • the interferon-sensitive disease is cancer.
  • a method of enhancing the immune response in a subject that has been administered a vaccine comprising administering to the subject an effective amount of a Compound, wherein the Compound has the formula:
  • R 1 of formula I is substituted or unsubstituted heterocyclyl; and R 2 of formula 1 is H or OH;
  • X of formula II is CH or N; and R 1 , R 2 , R 3 and R 4 of formula II are at each occurrence independently hydrogen or substituted or unsubstituted C 1-4 alkyl;
  • R 1 and R 2 of formula III are at each occurrence independently substituted or unsubstituted C 1-4 alkyl, or R 1 and R 2 of formula III taken together with the nitrogen atom to which they are attached form substituted or unsubstituted heterocyclyl; and
  • R 1 of formula IV is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and R 2 of formula IV is substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted C 2-4 alkenyl or substituted or unsubstituted heteroaryl.
  • R 1 of formula IV is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl
  • R 2 of formula IV is substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted C 2-4 alkenyl or substituted or unsubstituted heteroaryl.
  • R 1 of formula I is substituted tetrahydro-2H-pyran
  • R 1 , R 2 , R 3 and R 4 of formula II are methyl
  • R 1 and R 2 of formula III are each ethyl, or R 1 and R 2 of formula III taken together with the nitrogen atom to which they are attached form piperidine;
  • R 1 of formula IV is substituted or unsubstituted furan, thiophene or phenyl; and R 2 of formula IV is substituted or unsubstituted alkoxyalkyl, arylalkyl, allyl, propyl or alkoxyalkyl.
  • the subject is human.
  • a method for enhancing the immune response in a subject that has been administered a live virus vaccine comprising
  • a p armaceut ca y accepta e sa t or stereo somer, nc u ng enant omer, diastereomer, racemate or mixtures of stereoisomer, thereof.
  • the subject is human.
  • a method of enhancing the immune response in a subject that has been administered a live virus vaccine comprising
  • the subject is human.
  • a method of enhancing the immune response in a subject that has been administered a vaccine comprising administering to the subject an effective amount of a Compound, wherein the Compound has the structure:
  • the subject is human.
  • a method of enhancing the immune response in a subject that has been administered a vaccine comprising administering to the subject an effective amount of a Compound, wherein the Compound has the structure:
  • the subject is human.
  • the vaccine is an anthrax vaccine, BCG vaccine, Diphtheria vaccine, tetanus vaccine, pertussis vaccine, haemophilus B vaccine, hepatitis A vaccine, hepatitis B vaccine, human papillomavirus vaccine, influenza vaccine, Japanese encephalitis virus vaccine, measles vaccine, mumps vaccine, plague vaccine, pneumococcal vaccine, poliovirus vaccine, rabies vaccine, respiratory syncytial virus vaccine, rotavirus vaccine, rubella vaccine, smallpox vaccine, typhoid vaccine, varicella virus vaccine, yellow fever vaccine, or zoster vaccine.
  • the vaccine is an influenza vaccine.
  • a method for treating or preventing a viral disease in a subject in need thereof comprising administering to the subject an effective amount of a Compound, wherein the Compound has the structure:
  • the subject is human. In one embodiment, the subject is cancer-free.
  • the viral disease is caused by influenza virus, adenovirus, arbovirus, paramyxovirus, baculovirus, coronavirus, papillomavirus, parvovirus, chickenpox virus, reovirus, Ebola virus, Ebola-like virus, echo virus, encephalitis virus, filovirus, hantavirus, hepatitis virus, German measles virus, cytomegalovirus, hemorrhagic fever virus, herpes simplex virus, human immunodeficiency virus, human papillomavirus, human T cell leukemia virus, human T cell lymphoma virus, human T cell lymphotropic virus, Lassa fever virus, Marburg virus, measles virus, mumps virus, myxovirus, nairovirus, nanirnavirus, nariva virus, ndumo virus, Necrovirus, neethling virus, neopvirus, neurotropic
  • MDCK Madin-Darby canine kidney epithelial cell line that stably expresses the firefly luciferase enzyme under the strict regulation of the IFN beta promoter (MDCK- IFNb-Luc) was generated as previously described (see Hai et al., J Virol, 2008.
  • the MDCK-NS1 cell line stably expresses the A/PR/8/34 NSl protein fused to GFP.
  • MDCK cells, human embryonic kidney 293T cells, human alveolar basal epithelial (A549) cells, and African green monkey kidney (Vero) cells were obtained from the American Type Culture Collection (ATCC, Manassas, VA) and were maintained in Dulbecco's modified Eagle's medium (DMEM) or minimal essential medium (both from GIBCO, Carlsbad, CA), each supplemented with 10% fetal bovine serum (FBS) (HyClone, Logan, UT) and 1% penicillin-streptomycin (GIBCO).
  • DMEM Dulbecco's modified Eagle's medium
  • FBS fetal bovine serum
  • GIBCO penicillin-streptomycin
  • Influenza A/PR/8/34 virus was propagated in 10-day-old embryonated chicken eggs for 2 days at 37°C
  • Recombinant A/PR/8/34 NSl mutant virus deltaNSl (containing a complete deletion of the NS 1 expressing gene) was propagated in 6-day-old embryonated chicken eggs for 2 days at 37°C.
  • Other A/PR/8/34 NSl mutant viruses NSl -73 (expressing NSl amino acids 1-73), NSl-113 (expressing NS 1 amino acids 1-113), NSl-126 (expressing NSl amino acids 1-126) were propagated in 8-day-old embryonated chicken eggs for 2 days at 37°C.
  • Influenza A/WSN/33 virus was grown in MDCK cells in DMEM post-infection medium (DMEM supplemented with 0.3% bovine serum albumin (BSA), 0.1% FBS, lOmM HEPES, 1% penicillin-streptomycin, and lug mL TPCK).
  • A/WSN/33 with a deleted NSl protein was grown in MDCK-NS1 cells in DMEM post-infection medium. All wild-type influenza viruses were titered by standard plaque assay in MDCK cells. NS l mutant viruses were titered by plaque assay in the MDCK-NS1 cells.
  • VSV-GFP Vesicular stomatitis virus expressing the green fluorescence protein
  • ChemBridge Corp., San Diego, CA ChemDiv 2 (8,560 Compounds; ChemDiv, Inc., San Diego, CA), ChemDiv 4 (1 ,320 Compounds; ChemDiv, Inc., San Diego, CA), Enamine 2 (26,576 Compounds; ⁇ Ltd., Kiev, Ukraine), Life Chemicals 1 (3,893 Compounds; Life Chemicals Inc., Burlington, ON), Maybridge 4 (4,576 Compounds;
  • the Compounds were dissolved in DMSO at library-defined concentrations.
  • the primary screen was performed in 384-well format, using solid white 384-well tissue culture-treated plates (Corning Life Sciences, Lowell, MA).
  • MDCK-IFNb-Luc cells were cultured to 95% confluency, trypsinized with 0.05%> Trypsin-EDTA (Invitrogen Corp., Carlsbad, CA), and resuspended in phenol red-free DMEM growth medium supplemented with 5% FBS, and 1% penicillin-streptomycin at 2xl0 5 cells/mL. These were then transferred into 384-well plates using the Matrix Wellmate (Thermo Fisher Scientific Inc., Hudson, NH) plate filler.
  • Matrix Wellmate Thermo Fisher Scientific Inc., Hudson, NH
  • Loaded plates were centrifuged at lOOOrpm for 1 min to ensure that all cells and media were at the bottom of each well.
  • the cells were incubated for 20-24 hours at 37°C, 5% C0 2 before the addition of lOOnL of Compounds directly into each well by the Epson Compound transfer robot (Epson America, Inc., Long Beach, CA).
  • Epson America, Inc., Long Beach, CA Epson America, Inc., Long Beach, CA
  • the cells were incubated for 2 hours before infection with influenza A/PR/8/34 virus directly into the medium at an MOI of 10 using the Matrix Wellmate plate filler to transfer 5 ⁇ ⁇ of virus inoculum.
  • This virus was diluted from its stock concentration with phenol red- free DMEM growth medium supplemented with 1% penicillin-streptomycin, and 7 ⁇ g/mL TPCK (to achieve a final concentration o ⁇ ⁇ g/ L TPCK in each well containing a total volume of 35 ⁇ ). Infected plates were subsequently centrifuged at lOOOrpm for 1 min. Control wells were included in each plate and these did not contain Compounds. The negative control wells were infected with A/PR/8/34 virus and positive control wells were infected with A/PR/8/34 NSl-113 mutant virus. Infection was allowed to proceed for 18-20 hours at 37°C, 5% C0 2 . The plates were then removed from the incubator to equilibrate to room
  • Compound hits from the HTS were defined based on their Z-score. The criteria used included Compound that had a Z score of 3 and above, with its duplicate being at least 2.5.
  • the CellTiter-Glo ® Luminescent Cell Viability Assay (Promega Corp., Madison, WI) was used to detect cell viability in accordance with the manufacturer's specifications. Briefly, MDCK-IFNb-Luc cells were plated in solid white 96-well plates (Corning Life
  • Verification of Compound hits obtained from the primary HTS was performed applying the same HTS protocol.
  • the differences between the confirmation screen and the primary HTS are the following: 1) 96-well format was used, instead of 384-well format, 2) 10 different Compound concentrations were tested, using each Compound's CC 10 as the median concentration, 3) compound concentrations were tested for their ability to induce IFN in the presence and absence of A/PR/8/34 infection, 4) each set was done in triplicate.
  • Verification of the ability of the selected Compounds obtained in the confirmation screen to induce IFN production was performed in a functional interferon bioassay as previously described (see Park et al., J Virol, 2003. 77(2): 1501-11; and Iwata et al., J Vet Med Sci, 1996. 58(l):23-7), with some variations. Briefly, 96-well plates were seeded with MDCK cells at lxl 0 4 cells per well and allowed to incubate for 20-24 hours at 37°C, 5% C0 2 . These were then treated with Compounds at 5 different dilutions, starting from the dilution of maximum reporter signal obtained from the confirmation screen.
  • VSV-GFP vesicular stomatitis virus
  • MDCK cells were seeded onto 6-well plates and incubated for 24 hours at 37°C, 5% CO?. The cells were washed with PBS and the medium was replaced with DMEM postinfection media containing various concentrations of the Compound of interest. These were incubated for 2 hours prior to infection with A/PR/8/34 or A/WSN/33 viruses at an MOI of 0.01 or 0.001, respectively.
  • NS1 deleted mutant viruses (A/PR/8/34 delNSl and A/WSN/33 delNSl were used as negative controls for each wild type counterpart.
  • Various timepoints were taken during vims growth and monitored with standard hemagglutination (HA) assay.
  • a cell-based HTS assay was developed for the identification of small molecular weight Compounds that induce IFN-I in the presence of influenza virus infection.
  • An MDCK cell line that stably expresses the firefly luciferase enzyme under the strict regulation of the IFN beta promoter (MDCK-IFNb-Luc) was generated. Luciferase activity provides a measurement of the IFN beta response to influenza viruses expressing a non- functional NS 1 protein.
  • the cytoplasmic sensor retinoic acid-inducible gene I (RIG-I) is able to detect the 5 ' triphosphate moiety present in the RNA genome of influenza segments, and trigger downstream signaling, activating transcription factors, IRF3, NFkB, and API, required to turn on the IFNb promoter.
  • IRF3, NFkB, and API activating transcription factors
  • a positive readout in this screen will occur only in the presence of Compounds that target the NS1 molecule directly, host factors that are required for NS1 function, or modulators of the IFN beta production pathway independent of NS1 ( Figure 1).
  • This screen will also capture false positive hits, involving Compounds that induce general cellular transcription or stabilize the luciferase enzyme. These will be discarded in secondary assays.
  • This assay was initially optimized in 96-well format and its validity was confirmed by demonstrating a Z' factor (see Zhang et al., J Biomol Screen, 1999. 4(2):67-73) of at least 0.5.
  • the assay was further miniaturized and validated in 384-well format during a pilot screen conducted at the National Screening Laboratory for the Regional Centers of Excellence in Biodefense and Emerging Infectious Diseases (NSRB), housed at Harvard Medical School, using available robotic equipment for cell plating and Compound transfer.
  • confirmation screen was run manually in 96-well format for all 250 purchased Compounds.
  • the confirmation screen in contrast to the primary screen, tested 10 different Compound concentrations, 5 two-fold dilutions above and 5 two-fold dilutions below each Compound's CCio.
  • the confirmation screen also tested each Compound for induction of IFNb in the absence or presence of PR/8/34 infection, in order to identify Compounds that induce IFNb independent of a virus stimulus. From this confirmation screen, 27 Compounds that significantly induce the IFNb-Luc reporter were identified. Three Compounds induced IFNb in a virus-dependent manner, and the remaining 24 induced IFN independently of influenza virus infection ( Figure 3).
  • an IFN bioassay was performed.
  • Compound treated MDCK cells were subsequently mock infected or infected with A/PR/8/34 virus. Supernatants were collected and after UV inactivation, they were added to fresh MDCK cells in order to induce an antiviral state if IFN was present. After 24 hours incubation, the cells were infected with VSV-GFP, which is a virus sensitive to the effects of IFN. If the cells developed an antiviral state, VSV-GFP will not grow and no GFP signal will be detected.
  • ASN2 a Compound that requires virus infection in order to induce IFN in the reporter assay, is able to induce biologically relevant levels of IFN once the Compound- treated cells are also infected with A/PR/8/34. This IFN produced is capable of inhibiting growth of VSV-GFP (Fig 4).
  • Compounds that induce IFN were subsequently tested for their ability to inhibit multi-cycle replication of the A/PR/8/34 virus and A/WSN/33 influenza viruses.
  • an NS1 mutant virus was used, A/PR/8/34 delNSl and A/WSN/33 delNSl, respectively.
  • ASN2 (identified in Table 1 as Compound 1), a Compound that requires virus infection in order to induce IFN, is able to attenuate both A/PR/8/34 and A/WSN/33 virus replication in a dose-dependent manner.
  • ASN2 (Compound 1) to inhibit the replication of multiple influenza A virus subtypes was assessed using viral titer assays as described in Section 5.2.3.1.1, supra. Monolayers of A549 cells were infected with influenza virus at a multiplicity of 0.01 pfu and cultured in the presence or absence of various dilutions of ASN2 for 2 days.
  • Figure 6 demonstrates the antiviral activity of ASN2 against influenza A strain A/Vietnam/1203/2004 (H5N1).
  • Figure 7 demonstrates the antiviral activity of ASN2 against multiple influenza A virus strains.
  • ASN2 has broad antiviral activity against influenza A virus subtypes.
  • ASN2 capably inhibits replication of influenza A virus subtypes across many generations, i.e., ASN2 inhibits replication of influenza A virus subtypes from the year 1918 to the year 2009, as well as influenza A virus subtypes from intervening years ( Figure 7).
  • ASN2 affects the replication machinery of influenza virus.
  • Lipofectamine2000 (Invitrogen) with pCAGGS protein expression vectors encoding the PBl, PB2 and PA subunits of the viral polymerase (lOOng of each) and the nucleocapsid protein (200ng) of influenza virus strains A/WSN/33.
  • the transfection mix also contained the RNA polymerase II driven Renilla luciferase reporter pRLTK (Promega) (200ng) to normalize for transfection efficiency as well as the influenza virus-specific, RNA polymerase I driven, firefly luciferase reporter (pPolI Luc) (150ng).
  • Cells were cultured in DMEM which was supplemented 4 hours prior to the transfection with ASN2 or DMSO.
  • the transfection was performed in OptiMEM (Invitrogen), which was also supplemented with ASN2 or DMSO.
  • the OptiMEM was replaced 4 hours post transfection with DMEM containing ASN2 or DMSO.
  • DMEM containing ASN2 or DMSO.
  • After a 20-24 hour incubation period at 37°C and 5% C0 2 cells were harvested and lysed using the passive lysis buffer of the Dual Luciferase Assay Kit (Promega). Luminescence of firefly luciferase and Renilla luciferase was subsequently measured using the Dual Luciferase Assay Kit according to the specifications of the manufacturer.
  • Viral titer assays (see, e.g., Section 5.2.3.1.1 , supra) using cells that are type I interferon competent and type I interferon deficient demonstrated that the antiviral activity of ASN2 does not require the presence of type I interferon.
  • Interferon induction for the 24 identified virus-independent interferon-inducing compounds was assessed using an MDCK cell luciferase reporter system, as described in Sections 5.2.1 and 6.1.1.3, supra; cytotoxicity of the compounds was determined using the CellTiter-Glo ® Luminescent Cell Viability Assay (Promega Corp., Madison, WI), as described in Sections 5.2.2 and 6.1.1.5, supra. As demonstrated in Figure 10, several compounds possessed the ability to induce interferon while possessing minimal cytotoxicity.
  • Interferon induction by the 24 compounds in 293T and A549 cells was assessed using a luciferase reporter system, as described in Sections 5.2.1 and 6.1.1.3, supra.
  • Antiviral activity of the 24 compounds in 293T and A549 cells was assessed by infecting the cells with vesicular stomatitis virus (VSV) and analyzing the antiviral effect of the compounds as described in Section 6.1.1.7, supra.
  • VSV vesicular stomatitis virus

Abstract

La présente invention concerne des composés qui induisent la production d'interféron et des procédés d'identification de ces composés. La présente invention concerne en outre des compositions qui comprennent ces composés et des procédés d'utilisation de ces composés pour traiter des maladies sensibles à l'interféron telles que des infections virales, un cancer, et la sclérose en plaques.
PCT/US2011/023187 2010-02-01 2011-01-31 Composés induisant l'interféron et leurs utilisations WO2011094693A1 (fr)

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CN113896686A (zh) * 2021-10-09 2022-01-07 湖南师范大学 一种电压门控钠通道小分子抑制剂及其镇痛应用

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